Azepane- or Azocane-Substituted Pyrazoline Derivatives, Their Preparation and Use as Medicaments

ABSTRACT

The present invention relates to Azepane- or Azocane-substituted substituted pyrazoline compounds of formula (I), methods for their preparation, medicaments comprising these compounds as well as their use for the preparation of a medicament for the treatment of humans and animals

The present invention relates to Azepane- or Azocane-substitutedsubstituted pyrazoline compounds, methods for their preparation,medicaments comprising these compounds as well as their use for thepreparation of a medicament for the treatment of humans and animals.

Cannabinoids are compounds, which are derived from the cannabis sativaplant which is commonly known as marijuana. The most active chemicalcompound of the naturally occurring cannabinoids is tetrahydrocannabinol(THC), particularly Δ⁹-THC.

These naturally occurring cannabinoids as well as their syntheticanalogues promote their physiological effects via binding to specificG-coupled receptors, the so-called cannabinoid-receptors.

At present, two distinct types of receptors that bind both the naturallyoccurring and synthetic cannabinoids have been identified and cloned.These receptors, which are designated CB₁ and CB₂ are involved in avariety of physiological or pathophysiological processes in humans andanimals, e.g. processes related to the central nervous system, immunesystem, cardiovascular system, endocrinous system, respiratory system,the gastrointestinal tract or to reproduction, as described for example,in Hollister, Pharm. Rev. 38, 1986, 1-20; Reny and Singha, Prog. Drug.Res., 36, 71-114, 1991; Consroe and Sandyk, in Marijuana/Cannabinoids,Neurobiology and Neurophysiology, 459, Murphy L. and Barthe A. Eds., CRCPress, 1992.

Therefore, compounds, which have a high binding affinity for thesecannabinoid receptors and which are suitable for modulating thesereceptors are useful in the prevention and/or treatment ofcannabinoid-receptor related disorders.

In particular, the CB₁-Receptor is involved in many differentfood-intake related disorders such as bulimia or obesity, includingobesity associated with type II diabetes (non-insulin-dependentdiabetes) and thus, compounds suitable for regulating this receptor maybe used in the prophylaxis and/or treatment of these disorders.

Thus, it was an object of the present invention to provide novelcompounds for use as active substances in medicaments. In particular,these active substances should be suitable for the modulation ofCannabinoid receptors, more particularly for the modulation ofCannabinoid 1 (CB₁) receptors.

Said object was achieved by providing the Azepane- orAzocane-substituted pyrazoline compounds of general formula I givenbelow, their stereoisomers, corresponding salts and correspondingsolvates thereof.

It has been found that these compounds have a high affinity forcannabinoid receptors, particularly for the CB₁-receptor, and that theyact as modulators e.g. antagonists, inverse agonists or agonists onthese receptors. They are therefore suitable for the prophylaxis and/ortreatment of various disorders related to the central nervous system,the immune system, the cardiovascular system, the endocrinous system,the respiratory system, the gastrointestinal tract or reproduction inhumans and/or animals, preferably humans including infants, children andgrown-ups.

Thus, in one of its aspects the present invention relates to Azepane- orAzocane substituted pyrazoline compounds of general formula I,

-   -   wherein    -   Z is selected from C₁₋₄-Alkyl, substituted or unsubstituted,        branched or linear, saturated or unsaturated;    -   X and Y independently represent phenyl, thienyl, naphtyl or        pyridyl which groups may be substituted with 1, 2 or 3        substituents W, which can be the same or different, selected        from the group        -   branched or linear C₁₋₃-alkyl or branched or linear            C₁₋₃-alkoxy, phenyl, hydroxy, chloro, bromo, fluoro, iodo,            SH, trifluoromethyl, CHF₂, CH₂F, OCHF₂, trifluoromethylthio,            trifluoromethoxy, methylsulfonyl, carboxyl,            trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and            acetyl; O—P, with P denominating a prodrug group consisting            of aryl, C₈₋₂₀-alkyl, heteroaryl, C(O)—aryl,            C(O)-heteroaryl, C(O)—C₁₋₂₀-alkyl;    -   R⁸ representing a hydrogen atom or a branched or linear        C₁₋₃-alkyl group, while R⁹ is representing

-   -   -   with R⁵, R⁶ and R⁷ being independently from one another            selected from H, F, Cl, Br, I, OH, SH, C₁₋₄alkyl,            C₁₋₄alkoxy, CF₃, CHF₂, CH₂F, OCF₃, a keto-group, NO₂ or NH₂;            and n being 1 or 2;            or

    -   R⁸ and R⁹ together with the connecting Nitrogen atom are        representing

-   -   -   with R⁵, R⁶ and R⁷ being independently from one another            selected from H, F, Cl, Br, I, OH, SH, C₁₋₄alkyl,            C₁₋₄alkoxy, CF₃, CHF₂, CH₂F, OCF₃, a keto-group, NO₂ or NH₂;            and n being 1 or 2;

    -   optionally in the form of its racemate, pure stereoisomers,        especially enantiomers or diastereomers or in the form of        mixtures of stereoisomers, especially enantiomers or        diastereomers, in any suitable ratio; in the form shown or in        form of the acid or base or in form of a salt, especially a        physiologically acceptable salt, or in form of a solvate,        especially a hydrate or in form of a corresponding N-oxide        thereof.

In the context of this invention, alkyl radical or group is understoodas meaning saturated and unsaturated, linear or branched hydrocarbons,which can be unsubstituted or mono- or polysubstituted. Thus unsaturatedalkyl is understood to encompass alkenyl and alkinyl groups, like e.g.—CH═CH—CH₃ or —C≡C—CH₃, while saturated alkyl encompasses e.g. —CH₃ and—CH₂CH₃. In these radicals, C₁₋₂-alkyl represents C1- or C2-alkyl,C₁₋₃-alkyl represents C1-, C2- or C3-alkyl, C₁₋₄-alkyl represents C1-,C2-, C3- or C4-alkyl, C₁₋₅-alkyl represents C1-, C2-, C3-, C4-, orC5-alkyl, C₁₋₆-alkyl represents C1-, C2-, C3-, C4-, C5- or C6-alkyl,C₁₋₇alkyl represents C1-, C2-, C3-, C4-, C5-, C6- or C7-alkyl,C₁₋₈-alkyl represents C1-, C2-, C3-, C4, C5-, C6-, C7- or C8-alkyl,C₁₋₁₀-alkyl represents C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- orC₁₋₁₀-alkyl and C₁₋₁₈-alkyl represents C1-, C2-, C3-, C4, C5-, C6-, C7-,C8-, C9-, C10-, C11-, C12-, C13-, C14-, C15-, C16-, C17- or C18-alkyl.The alkyl radicals are preferably methyl, ethyl, vinyl (ethenyl),propyl, allyl (2-propenyl), 1-propinyl, methylethyl, butyl,1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl,1-methylpentyl, if substituted also CHF₂, CF₃ or CH₂OH etc.

In the context of this invention cycloalkyl radical or group isunderstood as meaning saturated and unsaturated (but not aromatic)cyclic hydrocarbons (without a heteroatom in the ring), which can beunsubstituted or mono- or polysubstituted. Furthermore, C₃₋₄-cycloalkylrepresents C3- or C4-cycloalkyl, C₃₋₅-cycloalkyl represents C3-, C4- orC5-cycloalkyl, C₃₋₆-cycloalkyl represents C3-, C4-, C5- orC6-cycloalkyl, C₃₋₇cycloalkyl represents C3-, C4-, C5-, C6- orC7-cycloalkyl, C₃₋₄-cycloalkyl represents C3-, C4-, C5-, C6-, C7- orC8-cycloalkyl, C₄₋₅-cycloalkyl represents C4- or C5-cycloalkyl,C₄₋₆-cycloalkyl represents C4-, C5- or C6-cycloalkyl, C₄₋₇-cycloalkylrepresents C4-, C5-, C6- or C7-cycloalkyl, C₄₋₈-cycloalkyl representsC4-, C5-, C6-C7- or C8-cycloalkyl C₅₋₆-cycloalkyl represents C5- orC6-cycloalkyl and C₅₋₇-cycloalkyl represents C5-, C6- or C7-cycloalkyl.However, mono- or polyunsaturated, preferably monounsaturated,cycloalkyls also in particular fall under the term cycloalkyl as long asthe cycloalkyl is not an aromatic system. The alkyl and cycloalkylradicals are preferably methyl, ethyl, vinyl (ethenyl), propyl, allyl(2-propenyl), 1-propinyl, methylethyl, butyl, 1-methylpropyl,2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl,cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl,cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, cyclooctyl, andalso adamantly.

In connection with alkyl or aliphatic group—unless defined otherwise—theterm substituted in the context of this invention is understood asmeaning replacement of at least one hydrogen radical by F, Cl, Br, I,NH₂, SH or OH, “polysubstituted” radicals being understood as meaningthat the replacement takes effect both on different and on the sameatoms several times with the same or different substituents, for examplethree times on the same C atom, as in the case of CF₃, or at differentplaces, as in the case of e.g. —CH(OH)—CH═CH—CHCl₂.

The term (CH₂)₃₋₆ is to be understood as meaning —CH₂—CH₂—CH₂—,—CH₂—CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—,(CH₂)₁₋₄ is to be understood as meaning —CH₂—, —CH₂—CH₂—, —CH₂—CH₂—CH₂—and —CH₂—CH₂—CH₂—CH₂—, (CH₂)₄₋₅ is to be understood as meaning—CH₂—CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—CH₂—CH₂—, etc.

An aryl radical or group is understood as meaning ring systems with atleast one aromatic ring but without heteroatoms even in only one of therings. Examples are phenyl, naphthyl, fluoranthenyl, fluorenyl,tetralinyl or indanyl, in particular 9H-fluorenyl or anthracenylradicals, which can be unsubstituted or monosubstituted orpolysubstituted.

In the context of this invention alkyl-aryl is understood as meaning anaryl group (see above) being connected to another atom through analkyl-group (see above) (preferably a C₁₋₄-alkyl), whereas the alkyl isalways saturated and linear or branched always refers to the alkyl.Examples include a benzyl-group

A heterocyclyl radical or group is understood as meaning heterocyclicring systems, saturated or unsaturated ring which contains one or moreheteroatoms from the group consisting of nitrogen, oxygen and/or sulfurin the ring and can also be mono- or polysubstituted. Examples which maybe mentioned from the group of heterocyclyls are furan, benzofuran,thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine,quinoline, isoquinoline, phthalazine, benzo-1,2,5-thiadiazole,benzothiazole, indole, benzotriazole, benzodioxolane, benzodioxane,carbazole and quinazoline.

In the context of this invention alkyl-heterocyclyl is understood asmeaning a heterocyclyl group (see above) being connected to another atomthrough an alkyl group (see above) (preferably a C₁₋₄-alkyl), whereasthe alkyl is always saturated and linear or branched always refers tothe alkyl.

In connection with aryl or alkyl-aryl, cycloalkyl or alkyl-cycloalkyl,heterocyclyl or alkyl-heterocyclyl, substituted is understood—unlessdefined otherwise—as meaning substitution of the ring-system of the arylor alkyl-aryl, cycloalkyl or alkyl-cycloalkyl; heterocyclyl oralkyl-heterocyclyl by OH, SH, ═O, halogen (F, Cl, Br, I), CN, NO₂, COOH;NR_(x)R_(y), with R_(x) and R_(y) independently being either H or asaturated or unsaturated, linear or branched, substituted orunsubstituted C₁₋₆-alkyl; a saturated or unsaturated, linear orbranched, substituted or unsubstituted C₁₋₆-alkyl; a saturated orunsaturated, linear or branched, substituted or unsubstituted—O—C₁₋₆-alkyl (alkoxy); a saturated or unsaturated, linear or branched,substituted or unsubstituted —S—C₁₋₆-alkyl; a saturated or unsaturated,linear or branched, substituted or unsubstituted —C(O)—C₁₋₆alkyl-group;a saturated or unsaturated, linear or branched, substituted orunsubstituted —C(O)—O—C₁₋₆-alkyl-group; a substituted or unsubstitutedaryl or alkyl-aryl; a substituted or unsubstituted cycloalkyl oralkyl-cycloalkyl; a substituted or unsubstituted heterocyclyl oralkyl-heterocyclyl.

The term “salt” is to be understood as meaning any form of the activecompound used according to the invention in which it assumes an ionicform or is charged and is coupled with a counter-ion (a cation or anion)or is in solution. By this are also to be understood complexes of theactive compound with other molecules and ions, in particular complexeswhich are complexed via ionic interactions.

The term “physiologically acceptable salt” means in the context of thisinvention any salt that is physiologically tolerated (most of the timemeaning not being toxic—especially not caused by the counter-ion) ifused appropriately for a treatment especially if used on or applied tohumans and/or mammals. These physiologically acceptable salts can beformed with cations or bases and in the context of this invention isunderstood as meaning salts of at least one of the compounds usedaccording to the invention—usually a (deprotonated) acid—as an anionwith at least one, preferably inorganic, cation which is physiologicallytolerated—especially if used on humans and/or mammals. The salts of thealkali metals and alkaline earth metals are particularly preferred, andalso those with NH4, but in particular (mono)- or (di)sodium, (mono)- or(di)potassium, magnesium or calcium salts.

These physiologically acceptable salts can also be formed with anions oracids in the context of this invention is understood as meaning salts ofat least one of the compounds used according to the invention—usuallyprotonated, for example on the nitrogen—as the cation with at least oneanion which are physiologically tolerated—especially if used on humansand/or mammals. By this is understood in particular, in the context ofthis invention, the salt formed with a physiologically tolerated acid,that is to say salts of the particular active compound with inorganic ororganic acids which are physiologically tolerated—especially if used onhumans and/or mammals. Examples of physiologically tolerated salts ofparticular acids are salts of: hydrochloric acid, hydrobromic acid,sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalicacid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaricacid, lactic acid or citric acid.

The compounds of the invention may be in crystalline form or either asfree compounds or as solvates and it is intended that those forms arewithin the scope of the present invention. Methods of solvation aregenerally known within the art. Suitable solvates are pharmaceuticallyacceptable solvates. The term “solvate” according to this invention isto be understood as meaning any form of the active compound according tothe invention in which this compound has attached to it via non-covalentbinding another molecule (most likely a polar solvent) especiallyincluding hydrates and alcoholates, e.g. methanolate.

Unless otherwise stated, the compounds of the invention are also meantto include compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonor ¹⁵N-enriched nitrogen are within the scope of this invention.

The compounds of formula (I) or their salts or solvates are preferablyin pharmaceutically acceptable or substantially pure form. Bypharmaceutically acceptable form is meant, inter alia, having apharmaceutically acceptable level of purity excluding normalpharmaceutical additives such as diluents and carriers, and including nomaterial considered toxic at normal dosage levels. Purity levels for thedrug substance are preferably above 50%, more preferably above 70%, mostpreferably above 90%. In a preferred embodiment it is above 95% of thecompound of formula (I) or, or of its salts, solvates or prodrugs.

In a preferred embodiment of the invention the Azepane- or Azocanesubstituted pyrazoline compounds according to the invention arecompounds of general formulas Ia or Ib,

-   -   wherein    -   Z is selected from C₁₋₄-Alkyl, substituted or unsubstituted,        branched or linear, saturated or unsaturated;    -   X and Y independently represent phenyl, thienyl, naphtyl or        pyridyl which groups may be substituted with 1, 2 or 3        substituents W, which can be the same or different, from the        group:        -   branched or linear C₁₋₃-alkyl or branched or linear            C₁₋₃-alkoxy, phenyl, hydroxy, chloro, bromo, fluoro, iodo,            SH, trifluoromethyl, CHF₂, CH₂F, OCHF₂, trifluoromethylthio,            trifluoromethoxy, methylsulfonyl, carboxyl,            trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and            acetyl; O—P, with P denominating a prodrug group consisting            of aryl, C₈₋₂₀-alkyl, heteroaryl, C(O)— aryl,            C(O)-heteroaryl, C(O)—C₁₋₂₀-alkyl;    -   R⁸ representing a hydrogen atom or a branched or linear        C₁₋₃-alkyl group, while R⁹ is representing

-   -   -   with R⁵, R⁶ and R⁷ being independently from one another            selected from H, F, Cl, Br, I, OH, SH, C₁₋₄alkyl,            C₁₋₄alkoxy, CF₃, CHF₂, CH₂F, OCF₃, a keto-group, NO₂ or NH₂;            and n being 1 or 2;            or

    -   R⁸ and R⁹ together with the connecting Nitrogen atom are        representing

-   -   -   with R⁵, R⁶ and R⁷ being independently from one another            selected from H, F, Cl, Br, I, OH, SH, C₁₋₄alkyl,            C₁₋₄alkoxy, CF₃, CHF₂, CH₂F, OCF₃, a keto-group, NO₂ or NH₂;            and being 1 or 2;

    -   optionally in the form shown or in form of the acid or base or        in form of a salt, especially a physiologically acceptable salt,        or in form of a solvate, especially a hydrate or in form of a        corresponding N-oxide thereof.

As there are 2 stereogenic centers in the molecules the compounds ofgeneral formulas Ia and Ib may actually show the following relativeconfiguration:

In a preferred embodiment of the invention the Azepane- or Azocanesubstituted pyrazoline compounds according to the invention arecompounds of general formula II,

-   -   wherein    -   Z′ is selected from C₁₋₄-Alkyl, substituted or unsubstituted,        branched or linear, saturated or unsaturated; preferably is        either CH₃ or C₂H₅;    -   R¹¹, R¹², R¹³ and R¹⁴ independently of one another represent: H;        branched or linear C₁₋₃-alkyl or branched or linear C₁₋₃-alkoxy,        phenyl, hydroxy, chloro, bromo, fluoro, iodo, SH,        trifluoromethyl, CHF₂, CH₂F, OCHF₂, trifluoromethylthio,        trifluoromethoxy, methylsulfonyl, carboxyl,        trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl;        O—P, with P denominating a prodrug group consisting of aryl,        C₈₋₂₀-alkyl, heteroaryl, C(O)-aryl, C(O)-heteroaryl,        C(O)—C₁₋₂₀-alkyl;    -   R¹⁸ representing a hydrogen atom or a branched or linear        C₁₋₃-alkyl group, while R¹⁹ is representing

-   -   -   with R¹⁵, R¹⁶ and R¹⁷ are independently from one another            selected from, H, F, Cl, Br, I, OH, SH, C₁₋₄alkyl,            C₁₋₄alkoxy, CF₃, CHF₂, CH₂F, OCF₃, a keto-group, NO₂ or NH₂;            and m being 1 or 2;            or

    -   R¹⁸ and R¹⁹ together with the connecting Nitrogen atom are        representing

-   -   -   with R¹⁵, R¹⁶ and R¹⁷ are independently from one another            selected from, H, F, Cl, Br, I, OH, SH, C₁₋₄alkyl,            C₁₋₄alkoxy, CF₃, CHF₂, CH₂F, OCF₃, a keto-group, NO₂ or NH₂;            and m being 1 or 2;

    -   optionally in the form of its racemate, pure stereoisomers,        especially enantiomers or diastereomers or in the form of        mixtures of stereoisomers, especially enantiomers or        diastereomers, in any suitable ratio; in the form shown or in        form of the acid or base or in form of a salt, especially a        physiologically acceptable salt, or in form of a solvate,        especially a hydrate or in form of a corresponding N-oxide        thereof.

In a preferred embodiment of the invention the Azepane- or Azocanesubstituted pyrazoline compounds according to the invention arecompounds of general formulas IIa or IIb,

-   -   wherein    -   Z′ is selected from C₁₋₄-Alkyl, substituted or unsubstituted,        branched or linear, saturated or unsaturated; preferably is        either CH₃ or C₂H₅;    -   R¹¹, R¹², R¹³ and R¹⁴ independently of one another represent: H;        branched or linear C₁₋₃-alkyl or branched or linear C₁₋₃-alkoxy,        phenyl, hydroxy, chloro, bromo, fluoro, iodo, SH,        trifluoromethyl, trifluoromethylthio, trifluoromethoxy, CHF₂,        CH₂F, OCHF₂, methylsulfonyl, carboxyl, trifluoromethylsulfonyl,        cyano, carbamoyl, sulfamoyl and acetyl; O—P, with P denominating        a prodrug group consisting of aryl, C₈₋₂₀-alkyl, heteroaryl,        C(O)-aryl, C(O)-heteroaryl, C(O)—C₁₋₂₀-alkyl;    -   R¹⁸ representing a hydrogen atom or a branched or linear        C₁₋₃-alkyl group, while R¹⁹ is representing

-   -   -   with R¹⁵, R¹⁶ and R¹⁷ are independently from one another            selected from, H, F, Cl, Br, I, OH, SH, C₁₋₄alkyl,            C₁₋₄alkoxy, CF₃, CHF₂, CH₂F, OCF₃, a keto-group, NO₂ or NH₂;            and m being 1 or 2;            or

    -   R¹⁸ and R¹⁹ together with the connecting Nitrogen atom are        representing

-   -   -   with R¹⁵, R¹⁶ and R¹⁷ are independently from one another            selected from, H, F, Cl, Br, I, OH, SH, C₁₋₄alkyl,            C₁₋₄alkoxy, CF₃, CHF₂, CH₂F, OCF₃, a keto-group, NO₂ or NH₂;            and m being 1 or 2;

    -   optionally in the form shown or in form of the acid or base or        in form of a salt, especially a physiologically acceptable salt,        or in form of a solvate, especially a hydrate or in form of a        corresponding N-oxide thereof.

In a preferred embodiment of the invention the Azepane- or Azocanesubstituted pyrazoline compounds of general formulas II, IIa or IIb,according to the invention are characterized in that

-   -   R¹¹, R¹², R¹³ and R¹⁴ independently of one another represent H,        CH₃, C₂H₅, C₃H₇, OCH₃, OC₂H₅, OH, SH, F, Cl, Br, I CF₃, CHF₂,        CH₂F, OCF₃, OCHF₂;    -   preferably    -   R¹¹, R¹², R¹³ and R¹⁴ independently of one another represent H,        OH, OCH₃, F, Cl, Br, I, CF₃, CHF₂ or OCF₃.

In a preferred embodiment of the invention the Azepane- or Azocanesubstituted pyrazoline compounds of general formulas II, IIa or IIb,according to the invention are characterized in that

-   -   R¹⁸ represents H.

In a preferred embodiment of the invention the Azepane- or Azocanesubstituted pyrazoline compounds of general formulas II, IIa or IIb,according to the invention are characterized in that

-   -   R¹⁵, R¹⁶ and R¹⁷ are independently from one another selected        from, H, F, Cl, Br, I, OH, CH₃, C₂H₅, OCH₃, OCF₃, or CF₃.

In a preferred embodiment of the invention the Azepane- or Azocanesubstituted pyrazoline compounds according to the invention arecompounds of general formula III,

-   -   wherein    -   Z″ is selected from CH₃ or C₂H₅;    -   R²¹, R²², R²³ and R²⁴ independently of one another represent: H;        branched or linear C₁₋₃-alkyl or branched or linear C₁₋₃-alkoxy,        phenyl, hydroxy, chloro, bromo, fluoro, iodo, SH,        trifluoromethyl, trifluoromethylthio, trifluoromethoxy,        methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano,        carbamoyl, sulfamoyl and acetyl; O—P, with P denominating a        prodrug group consisting of aryl, C₈₋₂₀-alkyl, heteroaryl,        C(O)-aryl, C(O)-heteroaryl, C(O)—C₁₋₂₀-alkyl;    -   R²⁸ representing a hydrogen atom or a branched or linear        C₁₋₃-alkyl group, while R²⁹ is representing

-   -   -   with R²⁵, R²⁶ and R²⁷ are independently from one another            selected from, H, F, Cl, Br, I, OH, SH, C₁₋₄alkyl,            C₁₋₄alkoxy, CF₃, CHF₂, CH₂F, OCF₃, a keto-group, NO₂ or NH₂;            p being 1 or 2;            or

    -   R²⁸ and R²⁹ together with the connecting Nitrogen atom are        representing

-   -   -   with R²⁵, R²⁶ and R²⁷ are independently from one another            selected from, H, F, Cl, Br, I, OH, SH, C₁₋₄alkyl,            C₁₋₄alkoxy, CF₃, CHF₂, CH₂F, OCF₃, a keto-group, NO₂ or NH₂;            p being 1 or 2;

    -   optionally in the form of its racemate, pure stereoisomers,        especially enantiomers or diastereomers or in the form of        mixtures of stereoisomers, especially enantiomers or        diastereomers, in any suitable ratio; in the form shown or in        form of the acid or base or in form of a salt, especially a        physiologically acceptable salt, or in form of a solvate,        especially a hydrate or in form of a corresponding N-oxide        thereof.

In a preferred embodiment of the invention the Azepane- or Azocanesubstituted pyrazoline compounds according to the invention arecompounds of general formulas IIIa or IIIb,

-   -   wherein    -   Z″ is selected from CH₃ or C₂H₅;    -   R²¹, R²², R²³ and R²⁴ independently of one another represent: H;        branched or linear C₁₋₃-alkyl or branched or linear C₁₋₃-alkoxy,        phenyl, hydroxy, chloro, bromo, fluoro, iodo, SH,        trifluoromethyl, trifluoromethylthio, trifluoromethoxy,        methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano,        carbamoyl, sulfamoyl and acetyl; O—P, with P denominating a        prodrug group consisting of aryl, C₈₋₂₀-alkyl, heteroaryl,        C(O)-aryl, C(O)-heteroaryl, C(O)—C₁₋₂₀-alkyl;    -   R²⁸ representing a hydrogen atom or a branched or linear        C₁₋₃-alkyl group, while R²⁹ is representing

-   -   -   with R²⁵, R²⁶ and R²⁷ are independently from one another            selected from, H, F, Cl, Br, I, OH, SH, C₁₋₄alkyl,            C₁₋₄alkoxy, CF₃, CHF₂, CH₂F, OCF₃, a keto-group, NO₂ or NH₂;            p being 1 or 2;            or

    -   R²⁸ and R²⁹ together with the connecting Nitrogen atom are        representing

-   -   -   with R²⁵, R²⁶ and R²⁷ are independently from one another            selected from, H, F, Cl, Br, I, OH, SH, C₁₋₄alkyl,            C₁₋₄alkoxy, CF₃, CHF₂, CH₂F, OCF₃, a keto-group, NO₂ or NH₂;            p being 1 or 2;

    -   optionally in the form shown or in form of the acid or base or        in form of a salt, especially a physiologically acceptable salt,        or in form of a solvate, especially a hydrate or in form of a        corresponding N-oxide thereof.

In a preferred embodiment of the invention the Azepane- or Azocanesubstituted pyrazoline compounds of general formulas III, IIIa or IIIb,according to the invention are characterized in that

-   -   R²¹ represents; O—P, with P denominating a prodrug group        consisting of aryl, C₈₋₂₀-alkyl, heteroaryl, C(O)-aryl,        C(O)-heteroaryl, C(O)—C₁₋₂₀-alkyl, while    -   R²², R²³ and R²⁴ independently of one another represent H, CH₃,        C₂H₅, C₃H₇, OCH₃, OC₂H₅, OH, SH, F, Cl, Br, I CF₃, CHF₂, CH₂F,        OCF₃, OCHF₂;    -   preferably    -   R²¹ represents; O—P, with P denominating a prodrug group        consisting of aryl, C₈₋₂₀-alkyl, heteroaryl, C(O)-aryl,        C(O)-heteroaryl, C(O)—C₁₋₂₀-alkyl, while    -   R²², R²³ and R²⁴ independently of one another represent H, OH,        OCH₃, F, Cl, Br, I, CF₃, CHF₂ or OCF₃;    -   most preferably    -   R²¹ represents; O—P, with P denominating a prodrug group        consisting of aryl, C₈₋₂₀-alkyl, heteroaryl, C(O)-aryl,        C(O)-heteroaryl, C(O)—C₁₋₂₀-alkyl, while    -   R²², R²³ and R²⁴ independently of one another represent OH,        OCH₃, F, Cl, Br, I or OCF₃.

In a preferred embodiment of the invention the Azepane- or Azocanesubstituted pyrazoline compounds of general formulas III, IIIa or IIIb,according to the invention are characterized in that

-   -   R²¹, R²², R²³ and R²⁴ independently of one another represent H,        CH₃, C₂H₅, C₃H₇, OCH₃, OC₂H₅, OH, SH, F, Cl, Br, I CF₃, CHF₂,        CH₂F, OCF₃, OCHF₂;    -   preferably    -   R²¹, R²², R²³ and R²⁴ independently of one another represent H,        OH, OCH₃, F, Cl, Br, I, CF₃, CHF₂ or OCF₃;    -   most preferably    -   R²¹ represents H, while R²², R²³ and R²⁴ independently of one        another represent OH, OCH₃, F, Cl, Br, I or OCF₃.

In a preferred embodiment of the invention the Azepane- or Azocanesubstituted pyrazoline compounds of general formulas III, IIIa or IIIb,according to the invention are characterized in that

-   -   R²⁸ represents H.

In a preferred embodiment of the invention the Azepane- or Azocanesubstituted pyrazoline compounds of general formulas III, IIIa or IIIb,according to the invention are characterized in that

-   -   R²⁵, R²⁶ and R²⁷ are independently from one another selected        from, H, F, Cl, Br, I, OH, CH₃, C₂H₅, OCH₃, OCF₃, or CF₃.

In a preferred embodiment of the invention the Azepane- or Azocanesubstituted pyrazoline compounds according to the invention arecompounds of general formulas IV, IVa or IVb,

-   -   wherein    -   Z′″ is selected from CH₃ or C₂H₅;    -   R³¹, R³², R³³ and R³⁴ independently of one another represent: H;        branched or linear C₁₋₃-alkyl or branched or linear C₁₋₃-alkoxy,        phenyl, hydroxy, chloro, bromo, fluoro, iodo, SH,        trifluoromethyl, trifluoromethylthio, trifluoromethoxy,        methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano,        carbamoyl, sulfamoyl and acetyl; O—P, with P denominating a        prodrug group consisting of aryl, C₈₋₂₀-alkyl, heteroaryl,        C(O)-aryl, C(O)-heteroaryl, C(O)—C₁₋₂₀-alkyl;    -   R³⁵, R³⁶ and R³⁷ are independently from one another selected        from, H, F, Cl, Br, I, OH, SH, C₁₋₄alkyl, C₁₋₄alkoxy, CF₃, CHF₂,        CH₂F, OCF₃, a keto-group, NO₂ or NH₂;    -   R³⁸ representing a hydrogen atom or a branched or linear        C₁₋₃-alkyl group;    -   optionally in the form shown or in form of the acid or base or        in form of a salt, especially a physiologically acceptable salt,        or in form of a solvate, especially a hydrate or in form of a        corresponding N-oxide thereof.

In a preferred embodiment of the invention the Azepane- or Azocanesubstituted pyrazoline compounds according to the invention arecompounds of general formulas IVc, IVd or IVe,

-   -   wherein    -   Z′″ is selected from CH₃ or C₂H₅;    -   R³¹, R³², R³³ and R³⁴ independently of one another represent:

H; branched or linear C₁₋₃-alkyl or branched or linear C₁₋₃-alkoxy,phenyl, hydroxy, chloro, bromo, fluoro, iodo, SH, trifluoromethyl,trifluoromethylthio, trifluoromethoxy, methylsulfonyl, carboxyl,trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl; O—P,with P denominating a prodrug group consisting of aryl, C₈₋₂₀-alkyl,heteroaryl, C(O)— aryl, C(O)-heteroaryl, C(O)—C₁₋₂₀-alkyl;

-   -   R³⁵, R³⁶ and R³⁷ are independently from one another selected        from, H, F, Cl, Br, I, OH, SH, C₁₋₄alkyl, C₁₋₄alkoxy, CF₃, CHF₂,        CH₂F, OCF₃, a keto-group, NO₂ or NH₂;    -   optionally in the form shown or in form of the acid or base or        in form of a salt, especially a physiologically acceptable salt,        or in form of a solvate, especially a hydrate or in form of a        corresponding N-oxide thereof.

In a preferred embodiment of the invention the Azepane- or Azocanesubstituted pyrazoline compounds of general formulas IV, IVa, IVb, IVc,IVd or IVe, according to the invention are characterized in that

-   -   R³¹ represents; O—P, with P denominating a prodrug group        consisting of aryl, C₈₋₂₀-alkyl, heteroaryl, C(O)-aryl,        C(O)-heteroaryl, C(O)—C₁₋₂₀-alkyl, while    -   R³², R³³ and R³⁴ independently of one another represent H, CH₃,        C₂H₅, C₃H₇, OCH₃, OC₂H₅, OH, SH, F, Cl, Br, I CF₃, CHF₂, CH₂F,        OCF₃, OCHF₂;    -   preferably    -   R³¹ represents; O—P, with P denominating a prodrug group        consisting of aryl, C₈₋₂₀-alkyl, heteroaryl, C(O)-aryl,        C(O)-heteroaryl, C(O)—C₁₋₂₀-alkyl, while    -   R³², R³³ and R³⁴ independently of one another represent H, OH,        OCH₃, F, Cl, Br, I, CF₃, CHF₂ or OCF₃;    -   most preferably    -   R³¹ represents; O—P, with P denominating a prodrug group        consisting of aryl, C₈₋₂₀-alkyl, heteroaryl, C(O)-aryl,        C(O)-heteroaryl, C(O)—C₁₋₂₀-alkyl, while    -   R³², R³³ and R³⁴ independently of one another represent OH,        OCH₃, F, Cl, Br, I or OCF₃.

In a preferred embodiment of the invention the Azepane- or Azocanesubstituted pyrazoline compounds of general formulas IV, IVa, IVb, IVc,IVd or IVe, according to the invention are characterized in that

-   -   R³¹, R³², R³³ and R³⁴ independently of one another represent H,        CH₃, C₂H₅, C₃H₇, OCH₃, OC₂H₅, OH, SH, F, Cl, Br, I CF₃, CHF₂,        CH₂F, OCF₃, OCHF₂;    -   preferably    -   R³¹, R³², R³³ and R³⁴ independently of one another represent H,        OH, OCH₃, F, Cl, Br, I, CF₃, CHF₂ or OCF₃;    -   most preferably    -   R³¹ represents H, while R³², R³³ and R³⁴ independently of one        another represent OH, OCH₃, F, Cl, Br, I or OCF₃.

In a preferred embodiment of the invention the Azepane- or Azocanesubstituted pyrazoline compounds of general formulas IV, IVa, IVb, IVc,IVd or IVe, according to the invention are characterized in that

-   -   R³⁸ represents H.

In a preferred embodiment of the invention the Azepane- or Azocanesubstituted pyrazoline compounds of general formulas IV, IVa, IVb, IVc,IVd or IVe, according to the invention are characterized in that

-   -   R³⁵, R³⁶ and R³⁷ are independently from one another selected        from, H, F, Cl, Br, I, OH, CH₃, C₂H₅, OCH₃, OCF₃, or CF₃.

In a preferred embodiment of the invention the Azepane- or Azocanesubstituted pyrazoline compounds of general formulas IV, IVa, IVbaccording to the invention are selected from the group consisting of:

-   -   •,    -   optionally in the form of its racemate, pure stereoisomers,        especially enantiomers or diastereomers or in the form of        mixtures of stereoisomers, especially enantiomers or        diastereomers, in any suitable ratio;    -   optionally in the form of a corresponding N-oxide, a        corresponding salt or a corresponding solvate.

In a preferred embodiment of the invention the Azepane- or Azocanesubstituted pyrazoline compounds of general formulas IVc, IVd or IVe,according to the invention are selected from the group consisting of:

-   -   •,    -   optionally in the form of its racemate, pure stereoisomers,        especially enantiomers or diastereomers or in the form of        mixtures of stereoisomers, especially enantiomers or        diastereomers, in any suitable ratio;    -   optionally in the form of a corresponding N-oxide, a        corresponding salt or a corresponding solvate.

In another aspect the present invention also provides a process for themanufacture of substituted pyrazoline compounds of general formula Iaccording to the invention, characterized in that at least onebenzaldehyde compound of general formula V

-   -   wherein X has the meaning as described above, is reacted with a        pyruvate compound of general formula (VI)

-   -   wherein Z has the meaning given above and G represents an OR        group with R being H or a branched or unbranched C₁₋₆ alkyl        radical or G represents an O⁻K group with K being a cation,    -   to yield a compound of general formula (VII)

-   -   wherein X and Z have the meaning given above, which is        optionally isolated and/or optionally purified, and which is        reacted with an optionally substituted phenyl hydrazine of        general formula (VII)

-   -   or a corresponding salt thereof, wherein Y has the meaning as        described above, under inert atmosphere, to yield a compound of        general formula (IX)

-   -   wherein X, Z and Y have the meaning as given above, which is        optionally isolated and/or optionally purified, and optionally        transferred under inert atmosphere to a compound of general        formula (XI) via the reaction with an activating agent

-   -   wherein the substituents X, Z and Y have the meaning given above        and A represents a leaving group, said compound being optionally        isolated and/or optionally purified, and at least one compound        of general formula (XI) is reacted with a compound of general        formula XIII or XIIa

-   -   wherein n, R⁵, R⁶, R⁷ and R⁸ are defined as described above;        under inert atmosphere to yield a substituted pyrazoline        compound of general formula I, which is optionally isolated        and/or optionally purified.

The inventive process is also illustrated in scheme I given below:

The reaction of the benzaldehyde compound of general formula V with apyruvate compound of general formula VI is preferably carried out in thepresence of at least one base, more preferably in the presence of analkali metal hydroxide such as sodium hydroxide or potassium hydroxideor an alkali metal methoxide such as sodium methoxide, as described, forexample, in Synthetic communications, 26(11), 2229-33, (1996). Therespective description is hereby incorporated by reference and formspart of the disclosure. Preferably sodium pyruvate may be used as thepyruvate compound. Preferably said reaction is carried out in a proticreaction medium such as a C₁₋₄ alkyl alcohol or mixtures of these.Mixtures of such alcohols with water, e.g. ethanol/water may also beused.

Reaction temperature as well as the duration of the reaction may varyover a broad range. Preferred reaction temperatures range from −10° C.to the boiling point of the reaction medium. Suitable reaction times mayvary for example from several minutes to several hours.

Also preferred the reaction of the benzaldehyde compound of generalformula V with a pyruvate compound of general formula VI is carried outunder acid catalysed conditions, more preferably by refluxing themixture in dichloromethane in the presence of copper(II)trifluoromethanesulfonate as described, for example, in Synlett, (1),147-149, 2001. The respective description is hereby incorporated byreference and forms part of the disclosure.

The reaction of the compound of general formula (VII) with an optionallysubstituted phenyl hydrazin of general formula (VIII) is preferablycarried out in a suitable reaction medium such as C₁₋₄-alcohols orethers such as dioxane or tetrahydrofurane or mixtures of at least twoof these afore mentioned compounds. Also preferably, said reaction maybe carried out in the presence of an acid, whereby the acid may beorganic such as acetic acid and/or inorganic such as hydrochloric acid.Furthermore, the reaction may also be carried out in the presence of abase such as piperidine, piperazine, sodium hydroxide, potassiumhydroxide, sodium methoxide or sodium ethoxide, or a mixture of at leasttwo of these bases may also be used.

Reaction temperature as well as the duration of the reaction may varyover a broad range. Suitable reaction temperatures range from roomtemperature, i.e. approximately 25° C. to the boiling point of thereaction medium. Suitable reaction times may vary for example fromseveral minutes to several hours.

The carboxylic group of the compound of general formula (IX) may beactivated for further reactions by the introduction of a suitableleaving group according to conventional methods well known to thoseskilled in the art. Preferably the compounds of general formula (IX) aretransferred into an acid chloride, an acid anhydride, a mixed anhydride,a C₁₋₄ alkyl ester, an activated ester such as p-nitrophenylester. Otherwell known methods for the activation of acids include the activationwith N,N-dicyclohexylcarbodiimide orbenzotriazol-N-oxotris(dimethylamino) phosphonium hexafluorophosphate(BOP)).

If said activated compound of general formula (XI) is an acid chloride,it is preferably prepared by reaction of the corresponding acid ofgeneral formula (IX) with thionyl chloride or oxalyl chloride, wherebysaid chlorinating agent is also used as the solvent. Also preferably anadditional solvent may be used. Suitable solvents include hydrocarbonssuch as benzene, toluene or xylene, halogenated hydrocarbons such asdichloromethane, chloroform or carbon tetrachloride, ethers such asdiethyl ether, dioxane, tetrahydrofurane or dimethoxyethane. Mixtures oftwo or more solvents from one class or two or more solvents fromdifferent classes may also be used. Preferred reaction temperature rangefrom 0° C. to the boiling point of the solvent and reaction times fromseveral minutes to several hours.

If said activated compound of general formula (XI) is a mixed anhydride,said anhydride may preferably be prepared, for example, by reaction ofthe corresponding acid of general formula (IX) with ethyl chloroformiatein the presence of a base such as triethylamine or pyridine, in asuitable solvent.

The afore mentioned reactions involving the synthesis of the4,5-dihydro-pyrazole ring or the reaction of a compound comprising saidring are carried out under an inert atmosphere, preferably nitrogen orargon, to avoid oxidation of the ring-system.

During the processes described above the protection of sensitive groupsor of reagents may be necessary and/or desirable. The introduction ofconventional protective groups as well as their removal may be performedby methods well-known to those skilled in the art.

If the substituted pyrazoline compounds of general formula (I)themselves are obtained in form of a mixture of stereoisomers,particularly enantiomers or diastereomers, said mixtures may beseparated by standard procedures known to those skilled in the art, e.g.chromatographic methods or fractionalized crystallization with chiralreagents. It is also possible to obtain pure stereoisomers viastereoselective synthesis.

In a further aspect the present invention also provides a process forthe preparation of salts of substituted pyrazoline compounds of generalformula (I) and stereoisomers thereof, wherein at least one compound ofgeneral formula (I) having at least one basic group is reacted with atleast one inorganic and/or organic acid, preferably in the presence of asuitable reaction medium. Suitable reaction media include, for example,any of the ones given above. Suitable inorganic acids includehydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid,nitric acid, suitable organic acids are e.g. citric acid, maleic acid,fumaric acid, tartaric acid, or derivatives thereof, p-toluenesulfonicacid, methanesulfonic acid or camphersulfonic acid.

In yet a further aspect the present invention also provides a processfor the preparation of salts of substituted pyrazoline compounds ofgeneral formula (I) or stereoisomers thereof, wherein at least onecompound of general formula (I) having at least one acidic group isreacted with one or more suitable bases, preferably in the presence of asuitable reaction medium. Suitable bases are e.g. hydroxides, carbonatesor alkoxides, which include suitable cations, derived e.g. from alkalinemetals, alkaline earth metals or organic cations, e.g. [NH_(n)R_(4-n)]⁺,wherein n is 0, 1, 2, 3 or 4 and R represents a branched or unbranchedC₁₋₄-alkyl-radical. Suitable reaction media are, for example, any of theones given above.

Solvates, preferably hydrates, of the substituted pyrazoline compoundsof general formula (I), of corresponding stereoisomers, of correspondingN-oxides or of corresponding salts thereof may also be obtained bystandard procedures known to those skilled in the art.

Substituted pyrazoline compounds of general formula I, which comprisenitrogen-atom containing saturated, unsaturated or aromatic rings mayalso be obtained in the form of their N-oxides by methods well known tothose skilled in the art.

Those skilled in the art understand that the term substituted pyrazolinecompounds as used herein is to be understood as encompassing derivativessuch as ethers, esters and complexes of these compounds as well. Theterm “derivatives” as used in this application is defined here asmeaning a chemical compound having undergone a chemical derivationstarting from an acting (active) compound to change (ameliorate forpharmaceutical use) any of its physico-chemical properties, especially aso-called prodrug, e.g. their esters and ethers. Examples of well knownmethods of producing a prodrug of a given acting compound are known tothose skilled in the art and can be found e.g. in Krogsgaard-Larsen etal., Textbook of Drugdesign and Discovery, Taylor & Francis (April2002). The respective description is hereby incorporated by referenceand forms part of the disclosure.

The purification and isolation of the inventive substituted pyrazolinecompounds of general formula (I), of a corresponding stereoisomer, orsalt, or N-oxide, or solvate or any intermediate thereof may, ifrequired, be carried out by conventional methods known to those skilledin the art, e.g. chromatographic methods or recrystallization.

The Azepane- or Azocane-substituted pyrazoline compounds of generalformula I given above, their stereoisomers, corresponding N-oxides,corresponding salts thereof and corresponding solvates aretoxicologically acceptable and are therefore suitable as pharmaceuticalactive substances for the preparation of medicaments.

It has been found that the Azepane- or Azocane-substituted pyrazolinecompounds of general formula I given above, stereoisomers thereof,N-oxides thereof, corresponding salts and corresponding solvates have ahigh affinity to cannabinoid receptors, particularly cannabinoid 1(CB₁)-receptors, i.e. they are selective ligands for the (CB₁)-receptorand act as modulators, e.g. antagonists, inverse agonists or agonists,on these receptors. In particular, these pyrazoline compounds showlittle or no development of tolerance during treatment, particularlywith respect to food intake, i.e. if the treatment is interrupted for agiven period of time and then continued afterwards, the inventively usedpyrazoline compounds will again show the desired effect. After endingthe treatment with the pyrazoline compounds, the positive influence onthe body weight is found to continue.

Furthermore, these Azepane- or Azocane-substituted pyrazoline compoundsshow relatively weak Herg channel affinity, thus a low risk ofprolongation of the QT-interval is to be expected for these compounds.

In summary, the inventively used 4-substituted pyrazoline compounds aredistinguished by a broad spectrum of beneficial effects, while at thesame time showing relatively little undesired effects, i.e. effectswhich do not positively contribute to or even interfere with the wellbeing of the patient.

Thus, an other aspect of the present invention relates to a medicamentcomprising at least one Azepane- or Azocane-substituted pyrazolinecompound of general formula I, optionally in form of one of itsstereoisomers, preferably enantiomers or diastereomers, a racemate or inform of a mixture of at least two of its stereoisomers, preferablyenantiomers and/or diastereomers, in any mixing ratio, or acorresponding N-oxide thereof, or a physiologically acceptable saltthereof, or a corresponding solvate thereof, and optionally at least onephysiologically acceptable auxiliary agent.

Preferably said medicament is suitable for the modulation (regulation)of cannabinoid-receptors, preferably cannabinoid 1 (CB₁) receptors, forthe prophylaxis and/or treatment of disorders of the central nervoussystem, disorders of the immune system, disorders of the cardiovascularsystem, disorders of the endocrinous system, disorders of therespiratory system, disorders of the gastrointestinal tract orreproductive disorders.

Particularly preferably said medicament is suitable for the prophylaxisand/or treatment of psychosis.

Also particularly preferably said medicament is suitable for theprophylaxis and/or treatment of food intake disorders, preferablybulimia, anorexia, cachexia, obesity and/or type II diabetes mellitus(non-insuline dependent diabetes mellitus), more preferably obesity. Theinventive medicament also seems to be active in the prophylaxis and/ortreatment of appetency disorders, e.g. the pyrazoline compounds ofgeneral formula I also reduce the desire for sweets.

Also particularly preferably said medicament is suitable for theprophylaxis and/or treatment of cancer, preferably for the prophylaxisand/or treatment of one or more types of cancer selected from the groupconsisting of brain cancer, bone cancer, lip cancer, mouth cancer,esophageal cancer, stomach cancer, liver cancer, bladder cancer,pancreas cancer, ovary cancer, cervical cancer, lung cancer, breastcancer, skin cancer, colon cancer, bowel cancer and prostate cancer,more preferably for the prophylaxis and/or treatment of one or moretypes of cancer selected from the group consisting of colon cancer,bowel cancer and prostate cancer.

Particularly preferably said medicament is suitable for the prophylaxisand/or treatment of alcohol abuse and/or alcohol addiction, nicotineabuse and/or nicotine addiction, drug abuse and/or drug addiction and/ormedicament abuse and/or medicament addiction, preferably drug abuseand/or drug addiction and/or nicotine abuse and/or nicotine addiction.

Medicaments and/or drugs, which are frequently the subject of misuseinclude opioids, barbiturates, cannabis, cocaine, amphetamines,phencyclidine, hallucinogens and benzodiazepines.

The medicament is also suitable for the prophylaxis and/or treatment ofone or more disorders selected from the group consisting of bonedisorders, preferably osteoporosis (e.g. osteoporosis associated with agenetic predisposition, sex hormone deficiency, or ageing),cancer-associated bone disease or Paget's disease of bone;schizophrenia, anxiety, depression, epilepsy, neurodegenerativedisorders, cerebellar disorders, spinocerebellar disorders, cognitivedisorders, cranial trauma, head trauma, stroke, panic attacks,peripheric neuropathy, inflammation, glaucoma, migraine, MorbusParkinson, Morbus Huntington, Morbus Alzheimer, Raynaud's disease,tremblement disorders, compulsive disorders, senile dementia, thymicdisorders, tardive dyskinesia, bipolar disorders, medicament-inducedmovement disorders, dystonia, endotoxemic shock, hemorrhagic shock,hypotension, insomnia, immunologic disorders, sclerotic plaques,vomiting, diarrhea, asthma, memory disorders, pruritus, pain, or forpotentiation of the analgesic effect of narcotic and non-narcoticanalgesics, or for influencing intestinal transit.

Another aspect of the present invention is the use of at least oneAzepane- or Azocane-substituted pyrazoline compound of general formula Igiven above as suitable active substances, optionally in form of one ofthe stereoisomers, preferably enantiomers or diastereomers, a racemateor in form of a mixture of at least two of the stereoisomers, preferablyenantiomers and/or diastereomers, in any mixing ratio, or acorresponding N-oxide thereof, or a corresponding salt thereof, or acorresponding solvate thereof, and optionally one or morepharmaceutically acceptable excipients, for the preparation of amedicament for the modulation of cannabinoid-receptors, preferablycannabinoid 1 (CB₁) receptors, for the prophylaxis and/or treatment ofdisorders of the central nervous system, disorders of the immune system,disorders of the cardiovascular system, disorders of the endocrinoussystem, disorders of the respiratory system, disorders of thegastrointestinal tract or reproductive disorders.

Particularly preferred is the use of at least one of the respectiveAzepane- or Azocane-substituted pyrazoline compounds, optionally in formof one of the stereoisomers, preferably enantiomers or diastereomers, aracemate or in form of a mixture of at least two of the stereoisomers,preferably enantiomers and/or diastereomers, in any mixing ratio, or acorresponding N-oxide thereof, or a corresponding salt thereof, or acorresponding solvate thereof, and optionally one or morepharmaceutically acceptable excipients, for the preparation of amedicament for the prophylaxis and/or treatment of psychosis.

Also particularly preferred is the use of at least one of the respectiveAzepane- or Azocane-substituted pyrazoline compounds, optionally in formof one of the stereoisomers, preferably enantiomers or diastereomers, aracemate or in form of a mixture of at least two of the stereoisomers,preferably enantiomers and/or diastereomers, in any mixing ratio, or acorresponding N-oxide thereof, or a corresponding salt thereof, or acorresponding solvate thereof, and optionally one or morepharmaceutically acceptable excipients, for the preparation of amedicament for the prophylaxis and/or treatment of food intakedisorders, preferably bulimia, anorexia, cachexia, obesity and/or typeII diabetes mellitus (non-insuline dependent diabetes mellitus), morepreferably obesity.

Also particularly preferred is the use of at least one of the pyrazolinecompounds as defined herein and optionally one or more pharmaceuticallyacceptable excipients, for the preparation of a medicament for thetreatment of metabolic syndrome.

The metabolic syndrome and definitions thereof are described in detailby Eckel et al., The Lancet, Vol. 365 (2005), 1415-1428, includedherewith by reference. One of the respective definitions was establishedby the WHO in 1998 (as described in Alberti et al., Diabet. Med. 1998,15, pages 539-53, the respective description thereof is herewithincorporated by reference and forms part of the present disclosure). Theother, more widely accepted, definition of the metabolic syndrome wasestablished by the Adult Treatment Panel (ATP III) of the US NationalCholesterol Education Program (NCEP) in 2001, as described in JAMA 2001;285; 2486-97, the respective description thereof is herewithincorporated by reference and forms part of the present disclosure.

The metabolic syndrome is characterized by an interaction of severalphysiological parameters such as triglycerides, lipids, blood pressure,glucose levels and insuline levels.

Even though obesity may play a critical role in the development ofmetabolic syndrome, many of its aspects are weight independent,especially some lipid parameters. Especially the positive influence onthe weight independent aspects of the metabolic syndrome (see e.g.Pagotto and Pasquali, The Lancet, Vol. 365 (2005), 1363, 1364, includedherewith by reference) like some blood parameters, especially lipidparameters is one of the major and surprising advantages of theinventively used substituted pyrazoline compounds.

Another aspect of the invention is the use of one or more pyrazolinecompounds as defined herein for the manufacture of a medicament forimprovement of cardiovascular and/or metabolic risk factors, such as oneor more of the following factors:

Elevated triglycerides, whereby elevated levels of triglycerides arepreferably understood as being >150 mg/dl,Low HDL cholesterol, whereby low levels of HDL cholesterol arepreferably understood as being <40 mg/dl in men and <50 mg/dl in women,Hypertension, whereby hypertension is preferably understood asbeing >130/85 mmHg,Impaired fasting glucose, whereby impaired fasting glucose levels arepreferably understood as being >110 mg/dl,Insulin resistance

Dyslipidemia.

Another aspect of the invention is the use of one or more pyrazolinecompounds as defined herein for the manufacture of a medicament for thetreatment of the weight independent aspects of metabolic syndrome.

Another aspect of the invention is a method for improving cardiovascularand/or metabolic risk factors, such as one or more of the followingfactors:

Elevated triglycerides, whereby elevated levels of triglycerides arepreferably understood as being >150 mg/dl,Low HDL cholesterol, whereby low levels of HDL cholesterol arepreferably understood as being <40 mg/dl in men and <50 mg/dl in women,Hypertension, whereby hypertension is preferably understood asbeing >130/85 mmHg,Impaired fasting glucose, whereby impaired fasting glucose levels arepreferably understood as being >110 mg/dl,Insulin resistance

Dyslipidemia,

in a subject, preferably a human.

Another aspect of the invention is a method for treating of the weightindependent aspects of metabolic-syndrome.

Also particularly preferred is the use of at least one of the respectiveAzepane- or Azocane-substituted pyrazoline compounds, optionally in formof one of the stereoisomers, preferably enantiomers or diastereomers, aracemate or in form of a mixture of at least two of the stereoisomers,preferably enantiomers and/or diastereomers, in any mixing ratio, or acorresponding N-oxide thereof, or a corresponding salt thereof, or acorresponding solvate thereof, and optionally one or morepharmaceutically acceptable excipients, for the preparation of amedicament for the prophylaxis and/or treatment of cancer, preferablyfor the prophylaxis and/or treatment of one or more types of cancerselected from the group consisting of brain cancer, bone cancer, lipcancer, mouth cancer, esophageal cancer, stomach cancer, liver cancer,bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lungcancer, breast cancer, skin cancer, colon cancer, bowel cancer andprostate cancer, more preferably for the prophylaxis and/or treatment ofone or more types of cancer selected from the group consisting of coloncancer, bowel cancer and prostate cancer.

Also particularly preferred is the use of at least one of the respectiveAzepane- or Azocane-substituted pyrazoline compounds, optionally in formof one of the stereoisomers, preferably enantiomers or diastereomers, aracemate or in form of a mixture of at least two of the stereoisomers,preferably enantiomers and/or diastereomers, in any mixing ratio, or acorresponding N-oxide thereof, or a corresponding salt thereof, or acorresponding solvate thereof, and optionally one or morepharmaceutically acceptable excipients, for the preparation of amedicament for the prophylaxis and/or treatment of alcohol abuse and/oralcohol addiction, nicotine abuse and/or nicotine addiction, drug abuseand/or drug addiction and/or medicament abuse and/or medicamentaddiction, preferably drug abuse and/or drug addiction and/or nicotineabuse and/or nicotine addiction.

Medicaments/drugs, which are frequently the subject of misuse includeopioids, barbiturates, cannabis, cocaine, amphetamines, phencyclidine,hallucinogens and benzodiazepines.

Also preferred is the use of at least one of the respective Azepane- orAzocane-substituted pyrazoline compounds, optionally in form of one ofthe stereoisomers, preferably enantiomers or diastereomers, a racemateor in form of a mixture of at least two of the stereoisomers, preferablyenantiomers and/or diastereomers, in any mixing ratio, or acorresponding N-oxide thereof, or a corresponding salt thereof, or acorresponding solvate thereof, and optionally one or morepharmaceutically acceptable excipients, for the preparation of amedicament for the prophylaxis and/or treatment of one or more disordersselected from the group consisting of bone disorders, preferablyosteoporosis (e.g. osteoporosis associated with a geneticpredisposition, sex hormone deficiency, or ageing), cancer-associatedbone disease or Paget's disease of bone; schizophrenia, anxiety,depression, epilepsy, neurodegenerative disorders, cerebella disorders,spinocerebellar disorders, cognitive disorders, cranial trauma, headtrauma, stroke, panic attacks, peripheric neuropathy, inflammation,glaucoma, migraine, Morbus Parkinson, Morbus Huntington, MorbusAlzheimer, Raynaud's disease, tremblement disorders, compulsivedisorders, senile dementia, thymic disorders, tardive dyskinesia,bipolar disorders, medicament-induced movement disorders, dystonia,endotoxemic shock, hemorrhagic shock, hypotension, insomnia, immunologicdisorders, sclerotic plaques, vomiting, diarrhea, asthma, memorydisorders, pruritus, pain, or for potentiation of the analgesic effectof narcotic and non-narcotic analgesics, or for influencing intestinaltransit.

The medicament according to the present invention may be in any formsuitable for the application to humans and/or animals, preferably humansincluding infants, children and adults and can be produced by standardprocedures known to those skilled in the art. The medicament can beproduced by standard procedures known to those skilled in the art, e.g.from the table of contents of “Pharmaceutics: The Science of DosageForms”, Second Edition, Aulton, M. E. (ED. Churchill Livingstone,Edinburgh (2002); “Encyclopedia of Pharmaceutical Technology”, SecondEdition, Swarbrick, J. and Boylan J. C. (Eds.), Marcel Dekker, Inc. NewYork (2002); “Modern Pharmaceutics”, Fourth Edition, Banker G. S. andRhodes C. T. (Eds.) Marcel Dekker, Inc. New York 2002 y “The Theory andPractice of Industrial Pharmacy”, Lachman L., Lieberman H. And Kanig J.(Eds.), Lea & Febiger, Philadelphia (1986). The respective descriptionsare hereby incorporated by reference and form part of the disclosure.The composition of the medicament may vary depending on the route ofadministration.

The medicament of the present invention may for example be administeredparentally in combination with conventional injectable liquid carriers,such as water or suitable alcohols. Conventional pharmaceuticalexcipients for injection, such as stabilizing agents, solubilizingagents, and buffers, may be included in such injectable compositions.These medicaments may for example be injected intramuscularly,intraperitoneally, or intravenously.

Medicaments according to the present invention may also be formulatedinto orally administrable compositions containing one or morephysiologically compatible carriers or excipients, in solid or liquidform. These compositions may contain conventional ingredients such asbinding agents, fillers, lubricants, and acceptable wetting agents. Thecompositions may take any convenient form, such as tablets, pellets,granules, capsules, lozenges, aqueous or oily solutions, suspensions,emulsions, or dry powdered forms suitable for reconstitution with wateror other suitable liquid medium before use, for immediate or retardedrelease. The multiparticulate forms, such as pellets or granules, maye.g. be filled into a capsule, compressed into tablets or suspended in asuitable liquid.

Suitable controlled release formulations, materials and methods fortheir preparation are known from the prior art, e.g. from the table ofcontents of “Modified-Release Drug Delivery Technology”, Rathbone, M. J.Hadgraft, J. and Roberts, M. S. (Eds.), Marcel Dekker, Inc., New York(2002); “Handbook of Pharmaceutical Controlled Release Technology”,Wise, D. L. (Ed.), Marcel Dekker, Inc. New York, (2000); “ControlledDrug Delivery”, Vol, I, Basic Concepts, Bruck, S. D. (Ed.), CRD PressInc., Boca Raton (1983) y de Takada, K. and Yoshikawa, H., “Oral DrugDelivery”, Encyclopedia of Controlled Drug Delivery, Mathiowitz, E.(Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 2, 728-742; Fix,J., “Oral drug delivery, small intestine and colon”, Encyclopedia ofControlled Drug Delivery, Mathiowitz, E. (Ed.), John Wiley & Sons, Inc.,New York (1999), Vol. 2, 698-728. The respective descriptions are herebyincorporated by reference and form part of the disclosure.

Medicaments according to the present invention may also comprise anenteric coating, so that their dissolution is dependent on pH-value. Dueto said coating the medicament can pass the stomach undissolved and therespective nitro-substituted phenyl-piperazine compound is liberated inthe intestinal tract. Preferably the enteric coating is soluble at a pHvalue of 5 to 7.5. Suitable materials and methods for the preparationare known from the prior art.

Typically, the medicaments according to the present invention maycontain 1-60% by weight of one or more Azepane- or Azocane-substitutedpyrazoline compounds as defined herein and 40-99% by weight of one ormore auxiliary substances (additives).

The liquid oral forms for administration may also contain certainadditives such as sweeteners, flavoring, preservatives, and emulsifyingagents. Non-aqueous liquid compositions for oral administration may alsobe formulated, containing edible oils. Such liquid compositions may beconveniently encapsulated in e.g., gelatin capsules in a unit dosageamount.

The compositions of the present invention may also be administeredtopically or via a suppository.

The daily dosage for humans and animals may vary depending on factorsthat have their basis in the respective species or other factors, suchas age, sex, weight or degree of illness and so forth. The daily dosagefor humans may preferably be in the range from 1 to 2000, preferably 1to 1500, more preferably 1 to 1000, even more preferably 1 to 150milligrams of active substance to be administered during one or severalintakes per day.

The present invention is illustrated below with the aid of examples.These illustrations are given solely by way of example and do not limitthe general spirit of the present invention.

EXAMPLES

The following compounds were prepared according to the general processesdescribed above. Those skilled in the art are familiar with the startingmaterials that are needed to obtain said compounds.

a) Preparation of compound of general formula(E)-4-(4-substituted-phenyl)-3-methyl (or 3-ethyl)-2-oxobut-3-enoic acid

-   -   (Where W has the meaning given above)

To a solution of aqueous 0.5 M NaOH (1.5 equivalents), under N₂ at roomtemperature, 2-oxobutyric acid (1.1 equivalents) is added in portions.The reaction is then left stirring for 5 min and a solution of4-substituted-benzaldehyde (1 equivalent) in abs. EtOH (0.9 M) is thenslowly added (10 mL/h). The reaction is left to stir at 25° C.overnight.

Water is added, and the solution evaporated under reduced pressure toeliminate the excess of EtOH. The solution is then washed with tolueneand evaporated (to eliminate traces of this solvent). The aqueoussolution is then cooled down in an ice bath and conc. HCl (0.2 mL ofconc HCl per mL of base) are slowly added under magnetically stirring. Awhite solid precipitates from the solution which is kept at 0° C. foranother hour. The solid is filtered under vacuum through a sinteredfunnel (porosity 3) and dried at 40° C. under vacuum. The yield rangefor this aldolic condensation is 60-86%.

If the starting material is 2-oxopentanoic acid (oxovaleric acid)instead of 2-oxobutyric acid, this reaction leads to(E)-4-(4-substituted-phenyl)-3-ethyl-2-oxobut-3-enoic acids, although inthis case, the yield of the reaction is slightly lower (around 40-50%)

(E)-4-(4-chlorophenyl)-3-methyl-2-oxobut-3-enoic acid

¹H NMR (400 MHz, CDCl₃): δ 2.17 (3H, s, CH₃), 7.44 (4H, ap d, J=3.28 Hz,ArH), 8.41 (1H, s, CH).

(E)-4-(4-bromophenyl)-3-methyl-2-oxobut-3-enoic acid

¹H NMR (400 MHz, CD₃OD): δ 1.99 (3H, s, CH₃), 7.36 (2H, d, J=8.5 Hz,ArH), 7.40 (1H, s, CH), 7.53 (2H, d, J=8.5 Hz, ArH).

(E)-4-(4-fluorophenyl)-3-methyl-2-oxobut-3-enoic acid

¹H NMR (300 MHz, DMSO-d6): δ 2.18 (3H, s, CH₃), 7.20 (2H, m), 7.53 (2H,m), 8.26 (1H, s, CH);

(E)-4-(4-methoxyphenyl)-3-methyl-2-oxobut-3-enoic acid. This compound isprepared following the method described above but using 3 eq of NaOHinstead of 1.5 eq.

¹H NMR (200 MHz, CDCl₃): δ 2.09 (3H, s, CH₃), 3.84 (3H, s, OCH₃), 7.01(2H, d, J=8.8 Hz, ArH), 7.50 (1H, s, CH), 7.52 (2H, d, J=8.8 Hz, ArH).

(E)-4-(4-bromophenyl)-3-ethyl-2-oxobut-3-enoic acid

¹H NMR (400 MHz, CDCl₃): δ 1.16 (3H, t, J=7.5 Hz, CH₃), 2.62 (2H, q,J=7.5 Hz, CH₂), 7.35 (2H, d, J=8.4 Hz, ArH), 7.59 (2H, d, J=8.4 Hz,ArH), 8.23 (1H, s, CH).

b) Preparation of compound of general formula cis or trans5-(4-substituted-phenyl)-1-(2,4-dichlorophenyl)-4-methyl (or4-ethyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid

-   -   (Where W has the meaning given above)

A suspension of 2,4-dichlorophenylhydrazine hydrochloride (1 equivalent)in glacial acetic acid (40 equivalents) is heated at 80° C. undernitrogen atmosphere. When the suspension becomes a solution, a solutionof (E)-4-(4-substituted-phenyl-3-methyl-2-oxo-3-butenoic acid (1equivalent) in acetic acid (20 equivalents) is added and the solutionleft to stir at 80° C. for 2 h.

Then, the mixture can be let crystallizing at 0-4° C. overnight aftersome concentration of acetic acid. The beige solid formed afterwards isfiltrated under vacuum through a sintered funnel (porosity 4) and washedseveral times with water. This crystallization process leads to themajor diastereoisomeric acid cis. The yield range for the cyclizationwith hydrazine to obtain the main diastereoisomer cis is around 46-60%.

If the starting material is(E)-4(4-substituted-phenyl)-3-ethyl-2-oxobut-3-enoic acid,cis-5-(4-substituted-phenyl)-1-(2,4-dichlorophenyl)-4-ethyl-4,5-dihydro-1H-pyrazole-3-carboxylicacid is obtained. In this case, the yield for the cyclization is around40%.

The reaction mixture can also be cooled down to room temperature andpoured through an addition funnel to water, cooled in an ice bath withmagnetically stirring. The addition must be slow and at least double thevolume of water per volume of acetic acid is required. It should form aprecipitate, but in the case a gum starts to be formed, it should befiltered and the rest of the material poured into another large volumeof water. The solid obtained is suspended in water several times andfiltered until the pH of the water is above 3. This solid alsocorresponds to the cis form.

Alternatively, the dark mixture can be extracted with dichloromethanewashed thoroughly with H₂O, dried over Na₂SO₄ and evaporated to dryness.Recrystallisation of the crude material with toluene (3 to 4 mL oftoluene per gram of material) allows the recovery of the majordiastereoisomer cis.

Formation of the methyl esters, followed by purification by columnchromatography, allows the separation of the two diastereoisomericforms. Then, a hydrolysis of the pure esters gives the correspondingacids cis and trans. Example: Methyl iodide (0.16 ml, 2.25 mmol) wasadded dropwise to a mixture of5-(4-chlorophenyl)-1-(2,4-dichlorophenyl>4-methyl-4,5-dihydro-1H-pyrazole-3-carboxylicacid (0.47 g, 1.27 mmol) and KHCO₃ (0.19 g, 1.9 mmol) in anhydrousdimethylformamide (10 ml) under nitrogen atmosphere. The mixture wasstirred at room temperature under nitrogen overnight (ca 16 h). Waterwas added, the mixture was extracted with ethyl acetate and the combinedorganic layers were thoroughly washed with aq. NaCl. After drying overNa₂SO₄ and evaporation under reduced pressure, 0.5 g of the crudeproduct were obtained. Purification by column chromatography (SiO₂, 40:1SiO₂, packed with 100% hexane and eluted with a gradient of 1% to 5%ethyl acetate) affords 0.045 g (9% yield) of the minor isomer (transracemic mixture) and 0.23 g (48% yield) of the major isomer (cis racemicmixture). Hydrolysis of the esters in the presence of NaOH leads to thecorresponding acids.

Another way to acids trans is described below:

To a stirred solution of 2,4-dichloroaniline (1 g, 6.17 mmol) andconcentrated hydrochloric acid (1.5 ml) in ice (1.5 ml) a solution ofNaNO₂ (0.460 mg, 6.68 mmol) in water (0.8 ml) is slowly added and themixture is stirred for 1 h at 0-5° C. Then, this solution is added overa cold mixture of NaOAc (1.64 g, 19.6 mmol), ethanol (26 ml) andethyl-2-chloro-3-oxobutanoate (1.0 g, 6.06 mmol) and let stirring for 1hour until the formed precipitate is collected by filtration, washedwith ethanol and dichloromethane and dried in vacuo to give the yellowsolid ethyl 2-chloro-2-(2-(2,4-dichlorophenyl)hydrazono)acetate (70-80%yield), which is used in the next step without any further purification.

Then, triethylamine (2.8 eq) is added to a solution of2-chloro-2-(2-(2,4-dichlorophenyl)hydrazono)acetate (1 eq) and a4-substituted trans-β-methylstyrene (3 eq) in toluene, and the mixtureis stirred at reflux temperature for 1 hour. The formed precipitate isremoved by filtration after cooling to room temperature. The filtrate isconcentrated and purified using a Combiflah system from Isco, elutingwith cyclohexane and ethyl acetate (in a gradient program until 30%AcOEt), to obtain pure ethyltrans-5-(4-substituted-phenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxylate,(˜40% yield). Another compound can be isolated from the purification,which is identified as the regioisomer ethyltrans-4-(4-substituted-phenyl)-1-(2,4-dichlorophenyl)-5-methyl-4,5-dihydro-1H-pyrazole-3-carboxylate(˜10% yield).

ethyltrans-4(4-substituted-phenyl)-1-(2,4-dichlorophenyl)-5-methyl-4,5-dihydro-1H-pyrazole-3-carboxylate

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.00 (d, J=6.6 Hz, 3H) 1.18 (t,J=7.2 Hz, 3H) 4.06 (d, J=3.3 Hz, 1H) 4.16 (m, 2H) 4.91 (m, 1H) 7.10-7.45(m, 8H)

Ethyltrans-5-(4-substituted-phenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxylateis hydrolyzed in the presence of aqueous 2 M NaOH (2 eq) andtetrahydrofuran for 4 hours. Then, tetrahydrofuran is partially removedby evaporation, 1 M HCl is added until pH is below 3 and the aqueousmixture is extracted with ethyl acetate, dried over Na₂SO₄, filtered andconcentrated in vacuo to yield a white solid identified astrans-5-(4-substituted-phenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxylicacid (85% yield). The resgioisomer ethyltrans-4-(4-substituted-phenyl)-1-(2,4-dichlorophenyl)-5-methyl-4,5-dihydro-1H-pyrazole-3-carboxylatecan be hydrolyzed in the same way.

The two enantiomers of each acid (cis or trans) can be separated bychiral HPLC or by crystallization of the diastereoisomeric salts formedwith chiral amines.

cis-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxylicacid

IR (KBr, cm⁻¹): 2976, 1682, 1566, 1542, 1490, 1270, 1242, 1117.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.96 (d, J=7.42 Hz, 3H) 3.82 (td,J=11.72, 7.42 Hz, 1H) 5.91 (d, J=11.72 Hz, 1H) 7.04 (d, J=8.60 Hz, 2H)7.11 (dd, J=8.60, 2.34 Hz, 1H) 7.21-7.30 (m, 4H)

¹³C NMR (100 MHz, CDCl₃): δ 13.6 (CH₃), 43.5 (CH), 72.0 (CH), 124.9(CH), 127.6 (CH), 129.1 (CH), 129.6 (CH), 130.9 (CH), 131.3 (C), 132.7(C), 134.5 (C), 138.7 (C), 144.6 (C), 165.9 (CO).

cis-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxylicacid

IR (KBr, cm⁻¹): 2976, 1683, 1541, 1486, 1385, 1270, 1242, 1116.

¹H NMR (400 MHz, CDCl₃): δ 0.96 (3H, d, J=7.3 Hz, CH₃), 3.82 (1H, qd,J=11.9, 7.3, 7.3, 7.3 Hz, 1H), 5.88 (1H, d, J=11.9 Hz, CH), 6.99 (2H, apd, J=8.4 Hz, ArH), 7.12 (1H, dd, J=8.7, 2.3 Hz, 1H), 7.17 (1H, m, ArH),7.27 (1H, m, ArH), 7.39 (2H, d, J=8.4 Hz, ArH).

cis-5-(4-fluorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxylicacid

IR (KBr, cm⁻¹): 2978, 1682, 1486, 1471, 1264, 1117.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.97 (d, J=7.42 Hz, 3H) 3.82 (td,J=11.72, 7.42 Hz, 1H) 5.91 (d, J=12.0 Hz, 1H), 6.95 (m, 2H), 7.10 (m,3H), 7.20 (d, J=9.0 Hz, 1H), 7.30 (d, J=3.0 Hz, 1H).

cis-5-(4-methoxyphenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxylicacid

IR (KBr, cm⁻¹): 2936, 2836, 1681, 1612, 1512, 1480, 1460, 1248, 1113.

¹H NMR (400 MHz, CDCl₃): δ 0.97 (3H, d, J=7.3 Hz, CH₃), 3.74 (3H, s,OCH₃), 3.80 (1H, m, 1H), 5.88 (1H, d, J=11.8 Hz, CH), 6.76 (2H, ap d,J=8.6 Hz, ArH), 7.00 (2H, d, J=8.6, ArH), 7.09 (1H, dd, J=8.6, 2.3 Hz,ArH), 7.16-7.28 (2H, m, ArH).

cis-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-4,5-dihydro-1H-pyrazole-3-carboxylicacid

IR (KBr, cm⁻¹): 2969, 1682, 1480, 1452, 1270, 1236, 1151, 1106.

¹H NMR (400 MHz, CDCl₃): δ 0.69 (3H, t, J=7.4 Hz, CH₃), 1.28-1.34 (1H,m, CHH), 1.95-2.00 (1H, m, CHH), 3.68 (1H, ddd, J=11.5, 9.7, 4.0 Hz,CH), 5.92 (1H, d, J=11.5 Hz, CH), 7.02 (2H, ap d, J=8.4 Hz, ArH), 7.09(1H, dd, J=8.7, 2.4 Hz, ArH), 7.20 (1H, d, J=8.7 Hz, ArH), 7.28 (1H, d,J=2.4 Hz, ArH), 7.36 (2H, ap d, J=8.4 Hz, ArH);

¹³C NMR (100 MHz, CDCl₃): δ 12.4 (CH₃), 20.0 (CH₂), 50.5 (CH₃), 52.3(OCH₃), 72.0 (CH), 122.5 (C), 124.8 (CH), 127.4 (C), 127.5 (CH), 129.9(CH), 130.4 (CH), 131.1 (C), 131.7 (CH), 132.7 (C), 138.5 (C), 143.8(C), 165.4 (CO).

trans-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxylicacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.52 (d, J=7.03 Hz, 3H) 3.52 (m,1H) 5.39 (d, J=5.47 Hz, 1H) 7.08 (ddd, J=13.92, 5.62, 5.28 Hz, 3H)7.14-7.34 (m, 4H)

¹³C NMR (100 MHz, CDCl₃): δ 18.4 (CH₃), 48.9 (CH), 76.2 (CH), 126.4(CH), 126.7 (C), 127.8 (CH), 128.0 (CH), 129.5 (CH), 130.5 (CH), 131.5(C), 134.7 (C), 137.6 (C), 138.6 (C), 144.2 (C), 166.5 (CO).

trans-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxylicacid

¹H NMR (400 MHz, CDCl₃): δ1.52 (3H, d, J=7.1 Hz, CH₃), 3.52 (1H, m, 1H),5.35 (1H, d, J=5.8 Hz, CH), 7.00 (2H, ap d, J=8.4 Hz, ArH), 7.10 (1H,dd, J=8.7, 2.3 Hz, 1H), 7.22 (1H, d, J=8.7, ArH), 7.27 (1H, d, J=2.3 Hz,ArH), 7.37 (2H, d, J=8.4 Hz, ArH).

(c) cis or trans5-(4-substituted-phenyl)-1-(2,4-dichlorophenyl)-4-methyl (or4-ethyl)-4,5-dihydro-1H-pyrazole-3-carbonyl chloride

-   -   (Where W has the meaning given above)

cis or trans 5-(4-substituted-phenyl)-1-(2,4-dichlorophenyl)-4-methyl(or 4-ethyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid (15 mmols)obtained according to step (b) was dissolved in 120 mL of dry tolueneand thionyl chloride (18 mmols) was added. The mixture is heated to 80°C. for 2.5 hours. The solvent is removed under reduced pressure and theresulting crude residue is used without any further purification.

cis-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carbonylchloride

IR (KBr, cm⁻¹): 1732, 1700, 1533, 1478, 1212, 826.

cis-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carbonylchloride

IR (KBr, cm⁻¹): 1731, 1527, 1477, 1204, 1153, 1132, 825, 802.

cis-5-(4-fluorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carbonylchloride

IR (KBr, cm⁻¹): 1731, 1509, 1478, 1227, 1153, 1132, 853, 803.

cis-5-(4-methoxyphenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carbonylchloride

IR (KBr, cm⁻¹): 1730, 1611, 1512, 1477, 1271, 1250, 1034, 831, 800.

cis-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-4,5-dihydro-1H-pyrazole-3-carbonylchloride

IR (KBr, cm⁻¹): 1728, 1526, 1478, 1227, 1200, 1153, 1129, 834, 801.

d)N-(azepan-1-yl)-5-(4-substituted-phenyl)-1-(2,4-dichlorophenyl)-4-methyl(or ethyl)-4,5-dihydro-1H-pyrazole-3-carboxamide orazepan-1-yl(5-(4-substituted-phenyl)-1-(2,4-dichlorophenyl)-4-methyl (orethyl)-4,5-dihydro-1H-pyrazol-3-yl)methanone andN-(azocan-1-yl)-5-(4-substituted-phenyl)-1-(2,4-dichlorophenyl)-4-methyl(or ethyl)-4,5-dihydro-1H-pyrazole-3-carboxamide orazocan-1-yl(5-(4-substituted-phenyl)-1-(2,4-dichlorophenyl)-4-methyl (orethyl)-4,5-dihydro-1H-pyrazol-3-yl)methanone

-   -   (Where W, R⁵, R⁶ and R⁷ have the meaning given above)

Under nitrogen atmosphere azepane, azocane, azepan-1-amine orazocane-1-amine (5.6 mmoles) and triethylamine (4 mL) were dissolved inmethylene chloride (25 mL). The resulting mixture was ice-cooled down to0° C. and a solution of cis or trans5-(4-substituted-phenyl)-1-(2,4-dichlorophenyl-4-methyl (orethyl)-4,5-dihydro-pyrazole-3-carboxylic acid chloride (4.6 mmoles)obtained in step (c) in methylene chloride (15 mL) was added dropwise.The resulting reaction mixture was stirred at room temperature(approximately 25° C.) overnight. Afterwards the reaction mixture waswashed with water, followed by a saturated aqueous solution of sodiumbicarbonate, then again with water, dried over sodium sulfate, filteredand evaporated to dryness in a rotavapor. A solution of 2 N HCl indiethyl ether or 2.8 N HCl in ethanol is added to the resulting crudeand let crystallizing from ethanol or ethyl acetate. The crystallizedsolid was removed via filtration and the mother liquors wereconcentrated to yield a second fraction of crystallized product. The twofractions were combined to give the desired product (yield range:60-80%).

If the starting material in step c) is a chiral acid, the startingconfiguration and ee are maintained in the final compounds.

Compounds where W═OH are prepared from the corresponding compounds withW═OMe by a cleavage with 2 M boron tribromide in dichloromethane (˜75%yield)

Example 1cis-N-(azepan-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxamidehydrochloride (1)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.78 (d, J=7.18 Hz, 3H) 1.58 (br. s.,4H) 1.76 (br. s., 4H) 3.32 (br. s, 4H) 3.85 (m, 1H) 5.95 (d, J=11.28 Hz,1H) 7.15 (d, J=8.50 Hz, 2H) 7.23-7.36 (m, 3H) 7.51 (d, J=2.34 Hz, 1H)7.61 (d, J=8.79 Hz, 1H) 10.89 (br. s., 1H)

Example 2cis-N-(azepan-1-yl)-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxamidehydrochloride (5)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.78 (d, J=7.18 Hz, 3H) 1.58 (br. s.,4H) 1.77 (br. s., 4H) 3.33 (br. s., 4H) 3.85 (dd, J=11.28, 7.18 Hz, 1H)5.94 (d, J=11.28 Hz, 1H) 7.08 (d, J=8.35 Hz, 2H) 7.34 (dd, J=8.72, 2.27Hz, 1H) 7.46 (d, J=8.35 Hz, 2H) 7.52 (d, J=2.34 Hz, 1H) 7.61 (d, J=8.64Hz, 1H) 10.98 (br. s., 1H)

Example 3cis-N-(azepan-1-yl)-5-(4-fluorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxamidehydrochloride (7)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.78 (d, J=7.32 Hz, 3H) 1.59 (br. s.,4H) 1.78 (br. s., 4H) 3.36 (br. s., 4H) 3.84 (dd, J=11.43, 7.32 Hz, 1H)5.96 (d, J=11.43 Hz, 1H) 6.99-7.21 (m, 4H) 7.33 (dd, J=8.79, 2.20 Hz,1H) 7.51 (d, J=2.34 Hz, 1H) 7.63 (d, J=8.79 Hz, 1H), 11.06 (br. s., 1H)

Example 4cis-N-(azepan-1-yl)-1-(2,4-dichlorophenyl)-5-(4-methoxyphenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxamidehydrochloride (9)

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.80 (d, J=7.18 Hz, 3H) 1.59 (br. s.,4H) 1.79 (br. s., 4H) 3.38 (d, J=4.54 Hz, 4H) 3.66 (s, 3H) 3.80 (dd,J=11.28, 7.32 Hz, 1H) 5.89 (d, J=11.28 Hz, 1H) 6.78 (d, J=8.50 Hz, 2H)7.03 (d, J=8.50 Hz, 2H) 7.32 (dd, J=8.79, 2.34 Hz, 1H) 7.49 (d, J=2.34Hz, 1H) 7.63 (d, J=8.79 Hz, 1H) 11.12 (br. s., 1H).

N^(o) STRUCTURE Autonom ¹H-NMR MS (M + H)⁺  1

cis-N-(azepan-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxamidehydrochloride 1H NMR (300 MHz, DMSO-d₆) δppm 0.78 (d, J = 7.18 Hz, 3H)1.58 (br. s., 4 H) 1.76 (br. s., 4 H)3.32 (br. s, 4 H) 3.85 (m, 1H)5.95 (d, J = 11.28 Hz, 1 H) 7.15(d, J = 8.50 Hz, 2 H) 7.23-7.36 (m,3H) 7.51 (d, J = 2.34 Hz, 1 H)7.61 (d, J = 8.79 Hz, 1 H) 10.89(br. s., 1H) 479  2

trans-N-(azepan-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxamidehydrochloride 479  3

(4R,5R)-N-(azepan-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxamidehydrochloride 479  4

(4S,5S)-N-(azepan-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxamidehydrochloride 479  5

cis-N-(azepan-1-yl)-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxamidehydrochloride 1H NMR (300 MHz, DMSO-d₆) δppm 0.78 (d, J = 7.18 Hz, 3H)1.58 (br. s., 4 H) 1.77 (br. s., 4 H)3.33 (br. s., 4 H) 3.85 (dd,J =11.28, 7.18 Hz, 1 H) 5.94 (d,J = 11.28 Hz, 1 H) 7.08 (d,J = 8.35 Hz, 2H) 7.34 (dd,J = 8.72, 2.27 Hz, 1 H) 7.46 (d,J = 8.35 Hz, 2 H) 7.52 (d, J= 2.34Hz, 1 H) 7.61 (d, J = 8.64 Hz, 1H) 10.98 (br. s., 1 H) 523  6

trans-N-(azepan-1-yl)-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxamidehydrochloride 523  7

cis-N-(azepan-1-yl)-5-(4-fluorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxamidehydrochloride 1H NMR (300 MHz, DMSO-d₆) δppm 0.78 (d, J = 7.32 Hz, 3H)1.59 (br. s., 4 H) 1.78 (br. s., 4 H)3.36 (br. s., 4 H) 3.84 (dd,J =11.43, 7.32 Hz, 1 H) 5.96 (d,J = 11.43 Hz, 1 H) 6.99-7.21 (m,4 H) 7.33(dd, J = 8.79, 2.20 Hz, 1H) 7.51 (d, J = 2.34 Hz, 1 H) 7.63(d, J = 8.79Hz, 1 H), 11.06 (br. s.,1 H) 463  8

trans-N-(azepan-1-yl)-5-(4-fluorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxamidehydrochloride 463  9

cis-N-(azepan-1-yl)-1-(2,4-dichlorophenyl)-5-(4-methoxyphenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxamidehydrochloride 1H NMR (300 MHz, DMSO-d₆) δppm 0.80 (d, J = 7.18 Hz, 3H)1.59 (br. s., 4 H) 1.79 (br. s., 4 H)3.38 (d, J = 4.54 Hz, 4 H) 3.66(s,3 H) 3.80 (dd, J = 11.28, 7.32 Hz,1 H) 5.89 (d, J = 11.28 Hz, 1H)6.78 (d, J = 8.50 Hz, 2 H) 7.03 (d,J = 8.50 Hz, 2 H) 7.32 (dd,J =8.79, 2.34 Hz, 1 H) 7.49 (d,J = 2.34 Hz, 1 H) 7.63 (d, J = 8.79Hz, 1 H)11.12 (br. s., 1 H) 475 10

trans-N-(azepan-1-yl)-1-(2,4-dichlorophenyl)-5-(4-methoxyphenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxamidehydrochloride 475 11

cis-N-(azepan-1-yl)-1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxamidehydrochloride 461 12

trans-N-(azepan-1-yl)-1-(2,4-dichlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxamidehydrochloride 461 13

azepan-1-yl-cis-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)methanone464 14

azepan-1-yl-trans-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)methanone464 15

cis-N-(azocan-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxamide493 16

trans-N-(azocan-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-3-carboxamide493 17

cis-azocan-1-yl((4S,5R)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)methanone478 18

trans-azocan-1-yl((4S,5R)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazol-3-yl)methanone478 19

cis-N-(azepan-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-4,5-dihydro-1H-pyrazole-3-carboxamidehydrochloride 493 20

trans-N-(azepan-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-4,5-dihydro-1H-pyrazole-3-carboxamidehydrochloride 493 21

cis-N-(azepan-1-yl)-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-4,5-dihydro-1H-pyrazole-3-carboxamidehydrochloride 537 22

trans-N-(azepan-1-yl)-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-4,5-dihydro-1H-pyrazole-3-carboxamidehydrochloride 537

Pharmacological Data: Pharmacological Methods I. In-Vitro Determinationof Affinity to CB1/CB2-Receptors

The in-vitro determination of the affinity of the inventive quaternaryammonium salts of substituted pyrazoline compounds to CB₁/CB₂-Rezeptorsis carried out as described in the publication of Ruth A. Ross, HeatherC. Brockie et al., “Agonist-inverse agonist characterization at CB₁ andCB₂ cannabinoid receptors of L-759633, L759656 and AM630”, BritishJournal of Pharmacology, 126, 665-672, (1999), whereby the transfectedhuman CB₁ and CB₂ receptors of Receptor Biology, Inc. are used. Theradioligand used for both receptors is [³H]-CP55940. The respectiveparts of the description are hereby incorporated by reference and formspart of the present disclosure.

Results:

The affinity of the inventive substituted pyrazoline compounds toCB₁/CB₂ receptors was determined as described above. Some of theEC50-values obtained are given in the table 3 below:

As can be seen from the values given in table 3 the inventive pyrazolinecompounds are particularly suitable for regulating the CB₁-Receptor.

II. In-Vivo Bioassay System for Determination of Cannabinoid ActivityMouse Tetrad Model

Substances with affinity for cannabinoid receptors are known to producea wide range of pharmacological effects. It is also known thatintravenous administration of a substance with affinity for cannabinoidreceptors in mice produces analgesia, hypothermia, sedation andcatalepsy. Individually, none of these effects can be considered asproof that a tested substance has affinity for cannabinoid-receptors,since all of these effects are common for various classes of centrallyactive agents. However, substances, which show all of these effects,i.e. substances that are active in this so-called tetrad model areconsidered to have affinity for the cannabinoid receptors. It hasfurther been shown that cannabinoid receptor antagonists are highlyeffective in blocking the effects of a cannabinoid agonist in the mousetetrad model.

The tetrad model is described, for example, in the publication of A. C.Howlett et al, International Union of Pharmacology XXVII. Classificationof Cannabinoid Receptors, Pharmacol Rev 54, 161-202, 2002 and David R.Compton et al., “In-vivo Characterization of a Specific CannabinoidReceptor Antagonist (SR141716A): Inhibition ofTetrahydrocannbinol-induced Responses and Apparent Agonist Activity”, J.Pharmacol. Exp. Ther. 277, 2, 586-594, 1996. The corresponding parts ofthe description are hereby incorporated by reference.

Material and Methods

Male NMRI mice with a weight of 20-30 g (Harlan, Barcelona, Spain) areused in all of the following experiments.

Before testing in the behavioral procedures given below, mice areacclimatized to the experimental setting. Pre-Treatment control valuesare determined for analgesia hot plate latency (in seconds), rectaltemperature, sedation and catalepsy.

In order to determine the agonistic activity of the substance to betested, the mice are injected intravenously with the substance to betested or the vehicle alone. 15 minutes after injection, latency in hotplate analgesia is measured.

Rectal temperature, sedation and catalepsy are measured 20 minutes afterinjection.

In order to determine the antagonistic activity the identical procedureis used as for the determination of the agonistic effects, but with thedifference that the substance to be evaluated for its antagonisticactivity is injected 5 minutes before the intravenous injection of 1.25mg/kg Win-55,212 a known cannabinoid-receptor agonist.

Hot Plate Analgesia

The hot plate analgesia is determined according to the method describedin Woolfe D. et al. “The evaluation of analgesic action of pethidinehydrochloride (Demerol)”, J. Pharmacol. Exp. Ther. 80, 300-307, 1944.The respective description is hereby incorporated by reference and formspart of the present disclosure. The mice are placed on a hot plate(Harvard Analgesimeter) at 55±0.5° C. until they show a painfulsensation by licking their paws or jumping and the time for thesesensations to occur is recorded. This reading is considered the basalvalue (B). The maximum time limit the mice are allowed to remain on thehot plate in absence of any painful response is 40 seconds in order toprevent skin damage. This period is called the cut-off time (PC).

Fifteen minutes after the administration of the substance to be tested,the mice are again placed on the hot plate and the afore describedprocedure is repeated. This period is called the post-treatment reading(PT).

The degree of analgesia is calculated from the formula:

% MPE of Analgesia=(PT−B)/(PC−B)×100

MPE=Maximum possible effect.

Determination of Sedation and Ataxia

Sedation and ataxia is determined according to the method described inDesmet L. K. C. et al. “Anticonvulsive properties of Cinarizine andFlunarizine in Rats and Mice”, Arzneim.-Forsch. (Frug Res) 25, 9, 1975.The respective description is hereby incorporated by reference and formspart of the present disclosure.

The chosen scoring system is

0: no ataxia;1: doubtful;2: obvious calmness and quiet;3 pronounced ataxia;prior to as well as after treatment.

The percentage of sedation is determined according to the formula:

% of sedation=arithmetic mean/3×100

Hypothermia:

Hypothermia is determined according to the method described in David R.Compton et al. “In-vivo Characterization of a Specific CannabinoidReceptor Antagonist (SR141716A) Inhibition ofTetrahydrocannbinol-induced Responses and Apparent Agonist Activity”, J.Pharmacol Exp Ther. 277, 2, 586-594, 1996. The respective description ishereby incorporated by reference and forms part of the presentdisclosure.

The base-line rectal temperatures are determined with a thermometer(Yello Springs Instruments Co., Panlabs) and a thermistor probe insertedto 25 mm before the administration of the substance to be tested. Rectaltemperature is again measured 20 minutes after the administration of thesubstances to be tested. The temperature difference is calculated foreach animal, whereby differences of ≧−2° C. are considered to representactivity.

Catalepsy:

Catalepsy is determined according to the method described in AlpermannH. G. et al. “Pharmacological effects of Hoe 249: A new potentialantidepressant”, Drugs Dev. Res. 25, 267-282.1992. The respectivedescription is hereby incorporated by reference and forms part of thepresent disclosure.

The cataleptic effect of the substance to be tested is evaluatedaccording to the duration of catalepsy, whereby the animals are placedhead downwards with their kinlegs upon the top of the wooden block.

The chosen scoring system is:

Catalepsy for:

more than 60 seconds=6; 50-60 seconds=5, 40-50 seconds=4, 30-40seconds=3, 20-30 seconds=2, 5-10 seconds=1, and less than 5 seconds=0.

The percentage of catalepsy is determined according of the followingformula:

% Catalepsy=arithmetic mean/6×100

Antagonistic Assay: Materials and Methods. Membrane Preparation:

Chinese hamster ovary (CHO) cells stably expressing recombinant humancannabinoid 1 receptor (CB1) were cultured in nutrient mixture Ham's F12 supplemented with 10% heat-inactivated fetal bovine serum, 2 mML-glutamine, 50 U/ml penicillin, 50 U/ml streptomycin and 0.5 mg/mlgeneticin. In order to obtain cells, culture flasks were washed twicewith phosphate buffered saline and scraped. Then, cells were collectedby centrifugation (200×g, 10 min) and stored dry at −80° C. Cells werehomogenized in ice-cold 20 mM HEPES, 10 mM EDTA (pH 7.5) and centrifugedat 40,000×g for 15 min at 4° C. The pellet was resuspended in 20 mMHEPES, 0.1 mM EDTA (pH 7.5) and centrifuged for 15 min at 4° C. Thefinal pellet was resuspended in 20 mM HEPES, 0.1 mM EDTA (pH 7.5), anddivided in aliquots and stored at −80° C. until use.

[³⁵S]GTPγS Binding Assay:

The reaction was performed in 96-well plates. Membranes (15 □gprotein/well) were incubated for 60 min at 30° C. in buffer (50 mMHEPES, 100 mM KCl, 5 mM MgCl₂, 1 mM EDTA, 0.1% wt/vol bovine serumalbumin, 50 mM GDP, saponin (10 μg/ml), 0.5 nM [³⁵S]GTPγS, pH 7.4) withcompound at 1 μM final concentration in either the absence or presenceof dose response curve of agonist WIN 55, 212-2 between 3 nM and 3 μM.The incubation was terminated by rapid filtration through MilliporeMultiscreen glass fiber FB, and rinsed two-times with ice-cold assaybuffer. Filter plates were dried and 30 μl of scintillation liquid wasadded. Radioactivity was determined using Wallac Microbeta Trilux. Eachexperiment was performed at least in duplicate. A WIN 55, 212-2dose-response was systematically performed.

Calculations:

The average of basal [³⁵S]GTPγS binding was subtracted from all bindingdata. In order to compare the antagonism results from one screeningcampaign to another one, the difference between the maximal agonisteffect of WIN 55, 212-2 alone, and the maximal antagonism effect due toWIN 55, 212-2 with an internal standard CB1-antagonist was defined as100%.

Results:

The determination of cannabinoid activity in-vivo was determined asdescribed above. The antagonistic effect (against Win 55212-2) wasdetermined for some of the compounds as given in the table 3 below:

The results of testing some of the above examples for binding andantagonism are shown together in the following table 3:

TABLE 3 Example IC50 (nM) Antagonism (%) 1 (HCl) 7.9 ± 2.8  99 ± 5 5 71± 2  133 ± 5 7 (HCl) 122  83 ± 6 7 52 9 (HCl)  61 117 ± 5

III. In Vivo Testing for Antiobesic Activity a) Acute-Treatment

Normally handled rats were habituated to a reversed cycle 12/12 h, andthe compound as well as saline was acutely orally administered. Afteradministration the cumulated food intake (g) was measured at 6 h and 23h. Following that the difference in body weight between control andcompound treated animals was measured.

The compounds (HCl-salts) according to example 1, 5 and 9 are active inthis model, reducing weight.

b) Long-Term-Treatment

The in-vivo testing for antiobesic activity of the inventive pyrazolinecompounds is carried out as described in the publication of G. Colomboet al., “Appetite Suppression and Weight Loss after the CannabinoidAntagonist SR 141716”; Life Sciences, 63 (8), 113-117, (1998). Therespective part of the description is hereby incorporated by referenceand forms part of the present disclosure.

IV. In Vivo Testing for Antidepressant Activity

The in-vivo testing for antidepressant activity of the inventivepyrazoline compounds in the water despair test is carried out asdescribed in the publication of E. T. Tzavara et al., “The CB1 receptorantagonist SR141716A selectively increases monoaminergicneurotransmission in the medial prefrontal cortex: implications fortherapeutic actions”; Br. J. Pharmacol. 2003, 138(4):544:53. Therespective part of the description is hereby incorporated by referenceand forms part of the present disclosure.

1. Azepane- or Azocane substituted pyrazoline compounds of generalformula I,

wherein Z is selected from C₁₋₄-Alkyl, substituted or unsubstituted,branched or linear, saturated or unsaturated; X and Y independentlyrepresent phenyl, thienyl, naphtyl or pyridyl which groups may besubstituted with 1, 2 or 3 substituents W, which can be the same ordifferent, selected from the group branched or linear C₁₋₃-alkyl orbranched or linear C₁₋₃-alkoxy, phenyl, hydroxy, chloro, bromo, fluoro,iodo, SH, trifluoromethyl, CHF₂, CH₂F, OCHF₂, trifluoromethylthio,trifluoromethoxy, methylsulfonyl, carboxyl, trifluoromethylsulfonyl,cyano, carbamoyl, sulfamoyl and acetyl; O—P, with P denominating aprodrug group consisting of aryl, C₈₋₂₀-alkyl, heteroaryl, C(O)-aryl,C(O)-heteroaryl, C(O)—C₁₋₂₀-alkyl; R⁸ representing a hydrogen atom or abranched or linear C₁₋₃-alkyl group, while R⁹ is representing

with R⁵, R⁶ and R⁷ being independently from one another selected from H,F, Cl, Br, I, OH, SH, C₁₋₄alkyl, C₁₋₄alkoxy, CF₃, CHF₂, CH₂F, OCF₃, aketo-group, NO₂ or NH₂; and n being 1 or 2; or R⁸ and R⁹ together withthe connecting Nitrogen atom are representing

with R⁵, R⁶ and R⁷ being independently from one another selected from H,F, Cl, Br, I, OH, SH, C₁₋₄alkyl, C₁₋₄alkoxy, CF₃, CHF₂, CH₂F, OCF₃, aketo-group, NO₂ or NH₂; and n being 1 or 2; optionally in the form ofits racemate, pure stereoisomers, especially enantiomers ordiastereomers or in the form of mixtures of stereoisomers, especiallyenantiomers or diastereomers, in any suitable ratio; in the form shownor in form of the acid or base or in form of a salt, especially aphysiologically acceptable salt, or in form of a solvate, especially ahydrate or in form of a corresponding N-oxide thereof.
 2. Azepane- orAzocane substituted pyrazoline compounds of general formulas Ia or Ibaccording to claim 1,

wherein Z is selected from C₁₋₄-Alkyl, substituted or unsubstituted,branched or linear, saturated or unsaturated; X and Y independentlyrepresent phenyl, thienyl, naphtyl or pyridyl which groups may besubstituted with 1, 2 or 3 substituents W, which can be the same ordifferent, from the group: branched or linear C₁₋₃-alkyl or branched orlinear C₁₋₃-alkoxy, phenyl, hydroxy, chloro, bromo, fluoro, iodo, SH,trifluoromethyl, CHF₂, CH₂F, OCHF₂, trifluoromethylthio,trifluoromethoxy, methylsulfonyl, carboxyl, trifluoromethylsulfonyl,cyano, carbamoyl, sulfamoyl and acetyl; O—P, with P denominating aprodrug group consisting of aryl, C₈₋₂₀-alkyl, heteroaryl, C(O)-aryl,C(O)-heteroaryl, C(O)—C₁₋₂₀-alkyl; R⁸ representing a hydrogen atom or abranched or linear C₁₋₃-alkyl group, while R⁹ is representing

with R⁵, R⁶ and R⁷ being independently from one another selected from H,F, Cl, Br, I, OH, SH, C₁₋₄alkyl, C₁₋₄alkoxy, CF₃, CHF₂, CH₂F, OCF₃, aketo-group, NO₂ or NH₂; and n being 1 or 2; or R⁸ and R⁹ together withthe connecting Nitrogen atom are representing

with R⁵, R⁶ and R⁷ being independently from one another selected from H,F, Cl, Br, I, OH, SH, C₁₋₄alkyl, C₁₋₄alkoxy, CF₃, CHF₂, CH₂F, OCF₃, aketo-group, NO₂ or NH₂; and being 1 or 2; optionally in the form shownor in form of the acid or base or in form of a salt, especially aphysiologically acceptable salt, or in form of a solvate, especially ahydrate or in form of a corresponding N-oxide thereof.
 3. Azepane- orAzocane substituted pyrazoline compounds of general formula II accordingto claim 1,

wherein Z′ is selected from C₁₋₄-Alkyl, substituted or unsubstituted,branched or linear, saturated or unsaturated; preferably is either CH₃or C₂H₅; R¹¹, R¹², R¹³ and R¹⁴ independently of one another represent:H; branched or linear C₁₋₃-alkyl or branched or linear C₁₋₃-alkoxy,phenyl, hydroxy, chloro, bromo, fluoro, iodo, SH, trifluoromethyl, CHF₂,CH₂F, OCHF₂, trifluoromethylthio, trifluoromethoxy, methylsulfonyl,carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl andacetyl; O—P, with P denominating a prodrug group consisting of aryl,C₈₋₂₀-alkyl, heteroaryl, C(O)-aryl, C(O)-heteroaryl, C(O)—C₁₋₂₀-alkyl;R¹⁸ representing a hydrogen atom or a branched or linear C₁₋₃-alkylgroup, while R¹⁹ is representing

with R¹⁵, R¹⁶ and R¹⁷ are independently from one another selected from,H, F, Cl, Br, I, OH, SH, C₁₋₄alkyl, C₁₋₄alkoxy, CF₃, CHF₂, CH₂F, OCF₃, aketo-group, NO₂ or NH₂; and m being 1 or 2; or R¹⁸ and R¹⁹ together withthe connecting Nitrogen atom are representing

with R¹⁵, R¹⁶ and R¹⁷ are independently from one another selected from,H, F, Cl, Br, I, OH, SH, C₁₋₄alkyl, C₁₋₄alkoxy, CF₃, CHF₂, CH₂F, OCF₃, aketo-group, NO₂ or NH₂; and m being 1 or 2; optionally in the form ofits racemate, pure stereoisomers, especially enantiomers ordiastereomers or in the form of mixtures of stereoisomers, especiallyenantiomers or diastereomers, in any suitable ratio; in the form shownor in form of the acid or base or in form of a salt, especially aphysiologically acceptable salt, or in form of a solvate, especially ahydrate or in form of a corresponding N-oxide thereof.
 4. Azepane- orAzocane-substituted pyrazoline compounds of general formulas IIa and IIbaccording to claim 3,

wherein Z′ is selected from C₁₋₄-Alkyl, substituted or unsubstituted,branched or linear, saturated or unsaturated; preferably is either CH₃or C₂H₅; R¹¹, R¹², R¹³ and R¹⁴ independently of one another represent:H; branched or linear C₁₋₃-alkyl or branched or linear C₁₋₃-alkoxy,phenyl, hydroxy, chloro, bromo, fluoro, iodo, SH, trifluoromethyl,trifluoromethylthio, trifluoromethoxy, CHF₂, CH₂F, OCHF₂,methylsulfonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl,sulfamoyl and acetyl; O—P, with P denominating a prodrug groupconsisting of aryl, C₈₋₂₀-alkyl, heteroaryl, C(O)-aryl, C(O)-heteroaryl,C(O)—C₁₋₂₀-alkyl; R¹⁸ representing a hydrogen atom or a branched orlinear C₁₋₃-alkyl group, while R¹⁹ is representing

with R¹⁵, R¹⁶ and R¹⁷ are independently from one another selected from,H, F, Cl, Br, I, OH, SH, C₁₋₄alkyl, C₁₋₄alkoxy, CF₃, CHF₂, CH₂F, OCF₃, aketo-group, NO₂ or NH₂; and m being 1 or 2; or R¹⁸ and R¹⁹ together withthe connecting Nitrogen atom are representing

with R¹⁵, R¹⁶ and R¹⁷ are independently from one another selected from,H, F, Cl, Br, I, OH, SH, C₁₋₄alkyl, C₁₋₄alkoxy, CF₃, CHF₂, CH₂F, OCF₃, aketo-group, NO₂ or NH₂; and m being 1 or 2; optionally in the form shownor in form of the acid or base or in form of a salt, especially aphysiologically acceptable salt, or in form of a solvate, especially ahydrate or in form of a corresponding N-oxide thereof.
 5. Azepane- orAzocane substituted pyrazoline compounds according to claim 3,characterized in that R¹¹, R¹², R¹³ and R¹⁴ independently of one anotherrepresent H, CH₃, C₂H₅, C₃H₇, OCH₃, OC₂H₅, OH, SH, F, Cl, Br, I CF₃,CHF₂, CH₂F, OCF₃, OCHF₂; preferably R¹¹, R¹², R¹³ and R¹⁴ independentlyof one another represent H, OH, OCH₃, F, Cl, Br, I, CF₃, CHF₂ or OCF₃.6. Azepane- or Azocane substituted pyrazoline compounds according toclaim 3, characterized in that R¹⁸ represents H.
 7. Azepane- or Azocanesubstituted pyrazoline compounds according to claim 3, characterized inthat R¹⁵, R¹⁶ and R¹⁷ are independently from one another selected from,H, F, Cl, Br, I, OH, CH₃, C₂H₅, OCH₃, OCF₃, or CF₃.
 8. Azepane- orAzocane substituted pyrazoline compounds of general formula IIIaccording to claim 1,

wherein Z″ is selected from CH₃ or C₂H₅; R²¹, R²², R²³ and R²⁴independently of one another represent: H; branched or linear C₁₋₃-alkylor branched or linear C₁₋₃-alkoxy, phenyl, hydroxy, chloro, bromo,fluoro, iodo, SH, trifluoromethyl, trifluoromethylthio,trifluoromethoxy, methylsulfonyl, carboxyl, trifluoromethylsulfonyl,cyano, carbamoyl, sulfamoyl and acetyl; O—P, with P denominating aprodrug group consisting of aryl, C₈₋₂₀-alkyl, heteroaryl, C(O)-aryl,C(O)-heteroaryl, C(O)—C₁₋₂₀-alkyl; R²⁸ representing a hydrogen atom or abranched or linear C₁₋₃-alkyl group, while R²⁹ is representing

with R²⁵, R²⁶ and R²⁷ are independently from one another selected from,H, F, Cl, Br, I, OH, SH, C₁₋₄alkyl, C₁₋₄alkoxy, CF₃, CHF₂, CH₂F, OCF₃, aketo-group, NO₂ or NH₂; p being 1 or 2; or R²⁸ and R²⁹ together with theconnecting Nitrogen atom are representing

with R²⁵, R²⁶ and R²⁷ are independently from one another selected from,H, F, Cl, Br, I, OH, SH, C₁₋₄alkyl, C₁₋₄alkoxy, CF₃, CHF₂, CH₂F, OCF₃, aketo-group, NO₂ or NH₂; p being 1 or 2; optionally in the form of itsracemate, pure stereoisomers, especially enantiomers or diastereomers orin the form of mixtures of stereoisomers, especially enantiomers ordiastereomers, in any suitable ratio; in the form shown or in form ofthe acid or base or in form of a salt, especially a physiologicallyacceptable salt, or in form of a solvate, especially a hydrate or inform of a corresponding N-oxide thereof.
 9. Azepane- or Azocanesubstituted pyrazoline compounds of general formulas IIIa and IIIbaccording to claim 8,

wherein Z″ is selected from CH₃ or C₂H₅; R²¹, R²², R²³ and R²⁴independently of one another represent: H; branched or linear C₁₋₃-alkylor branched or linear C₁₋₃-alkoxy, phenyl, hydroxy, chloro, bromo,fluoro, iodo, SH, trifluoromethyl, trifluoromethylthio,trifluoromethoxy, methylsulfonyl, carboxyl, trifluoromethylsulfonyl,cyano, carbamoyl, sulfamoyl and acetyl; O—P, with P denominating aprodrug group consisting of aryl, C₈₋₂₀-alkyl, heteroaryl, C(O)-aryl,C(O)-heteroaryl, C(O)—C₁₋₂₀-alkyl; R²⁸ representing a hydrogen atom or abranched or linear C₁₋₃-alkyl group, while R²⁹ is representing

with R²⁵, R²⁶ and R²⁷ are independently from one another selected from,H, F, Cl, Br, I, OH, SH, C₁₋₄alkyl, C₁₋₄alkoxy, CF₃, CHF₂, CH₂F, OCF₃, aketo-group, NO₂ or NH₂; p being 1 or 2; or R²⁸ and R²⁹ together with theconnecting Nitrogen atom are representing

with R²⁵, R²⁶ and R²⁷ are independently from one another selected from,H, F, Cl, Br, I, OH, SH, C₁₋₄alkyl, C₁₋₄alkoxy, CF₃, CHF₂, CH₂F, OCF₃, aketo-group, NO₂ or NH₂; p being 1 or 2; optionally in the form shown orin form of the acid or base or in form of a salt, especially aphysiologically acceptable salt, or in form of a solvate, especially ahydrate or in form of a corresponding N-oxide thereof.
 10. Azepane- orAzocane substituted pyrazoline compounds according to claim 8,characterized in that R²¹ represents; O—P, with P denominating a prodruggroup consisting of aryl, C₈₋₂₀-alkyl, heteroaryl, C(O)-aryl,C(O)-heteroaryl, C(O)—C₁₋₂₀-alkyl, while R²², R²³ and R²⁴ independentlyof one another represent H, CH₃, C₂H₅, C₃H₇, OCH₃, OC₂H₅, OH, SH, F, Cl,Br, I CF₃, CHF₂, CH₂F, OCF₃, OCHF₂; preferably R²¹ represents; O—P, withP denominating a prodrug group consisting of aryl, C₈₋₂₀-alkyl,heteroaryl, C(O)-aryl, C(O)-heteroaryl, C(O)—C₁₋₂₀-alkyl, while R²², R²³and R²⁴ independently of one another represent H, OH, OCH₃, F, Cl, Br,I, CF₃, CHF₂ or OCF₃; most preferably R²¹ represents; O—P, with Pdenominating a prodrug group consisting of aryl, C₈₋₂₀-alkyl,heteroaryl, C(O)-aryl, C(O)-heteroaryl, C(O)—C₁₋₂₀-alkyl, while R²², R²³and R²⁴ independently of one another represent OH, OCH₃, F, Cl, Br, I orOCF₃.
 11. Azepane- or Azocane substituted pyrazoline compounds accordingto claim 8, characterized in that R²¹, R²², R²³ and R²⁴ independently ofone another represent H, CH₃, C₂H₅, C₃H₇, OCH₃, OC₂H₅, OH, SH, F, Cl,Br, I CF₃, CHF₂, CH₂F, OCF₃, OCHF₂; preferably R²¹, R²², R²³ and R²⁴independently of one another represent H, OH, OCH₃, F, Cl, Br, I, CF₃,CHF₂ or OCF₃; most preferably R²¹ represents H, while R²², R²³ and R²⁴independently of one another represent OH, OCH₃, F, Cl, Br, I or OCF₃.12. Azepane- or Azocane substituted pyrazoline compounds according toclaim 8, characterized in that R²⁸ represents H. 13-21. (canceled) 22.Process for the manufacture of substituted pyrazoline compounds ofgeneral formula I according to claim 1, characterized in that at leastone benzaldehyde compound of general formula V

wherein X has the meaning according to claim 1, is reacted with apyruvate compound of general formula (VI)

wherein Z has the meaning according to claim 1 and G represents an ORgroup with R being H or a branched or unbranched C₁₋₆ alkyl radical or Grepresents an O⁻K group with K being a cation, to yield a compound ofgeneral formula (VII)

wherein X and Z have the meaning given above, which is optionallyisolated and/or optionally purified, and which is reacted with anoptionally substituted phenyl hydrazine of general formula (VIII)

or a corresponding salt thereof, wherein Y has the meaning according toclaim 1, under inert atmosphere, to yield a compound of general formula(IX)

wherein X, Z and Y have the meaning as given above, which is optionallyisolated and/or optionally purified, and optionally transferred underinert atmosphere to a compound of general formula (XI) via the reactionwith an activating agent

wherein the substituents X, Z and Y have the meaning given above and Arepresents a leaving group, said compound being optionally isolatedand/or optionally purified, and at least one compound of general formula(XI) is reacted with a compound of general formula XII or XIIa

wherein n, R⁵, R⁶, R⁷ and R⁸ are defined as in claim 1; under inertatmosphere to yield a substituted pyrazoline compound of general formulaI, which is optionally isolated and/or optionally purified. 23.Medicament comprising at least one substituted pyrazoline compound ofgeneral formula I according to claim 1, and optionally one or morepharmaceutically acceptable excipients.
 24. A method for the modulationof cannabinoid-receptors, preferably cannabinoid 1 (CB₁) receptors, forthe prophylaxis and/or treatment of disorders of the central nervoussystem, disorders of the immune system, disorders of the cardiovascularsystem, disorders of the endocrinous system, disorders of therespiratory system, disorders of the gastrointestinal tract orreproductive disorders the method comprising administering to a patienta compound of claim
 1. 25. A method for the prophylaxis and/or treatmentof food intake disorders, preferably bulimia, anorexia, cachexia,obesity, type II diabetes mellitus (non-insuline dependent diabetesmellitus), more preferably obesity the method comprising administeringto a patient a compound of claim
 1. 26. A method for the prophylaxisand/or treatment of psychosis the method comprising administering to apatient a compound of claim
 1. 27. A method for the prophylaxis and/ortreatment of alcohol abuse and/or alcohol addiction, nicotine abuseand/or nicotine addiction, drug abuse and/or drug addiction and/ormedicament abuse and/or medicament addiction, preferably drug abuseand/or drug addiction and/or nicotine abuse and/or nicotine addictionthe method comprising administering to a patient a compound of claim 1.28. A method for the prophylaxis and/or treatment of cancer, preferablyfor the prophylaxis and/or treatment of one or more types of cancerselected from the group consisting of brain cancer, bone cancer, lipcancer, mouth cancer, esophageal cancer, stomach cancer, liver cancer,bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lungcancer, breast cancer, skin cancer, colon cancer, bowel cancer andprostate cancer, more preferably for the prophylaxis and/or treatment ofone or more types of cancer selected from the group consisting of coloncancer, bowel cancer and prostate cancer the method comprisingadministering to a patient a compound of claim
 1. 29. A method for theprophylaxis and/or treatment of one or more disorders selected from thegroup consisting of bone disorders, preferably osteoporosis (e.g.osteoporosis associated with a genetic predisposition, sex hormonedeficiency, or ageing), cancer-associated bone disease or Paget'sdisease of bone; schizophrenia, anxiety, depression, epilepsy,neurodegenerative disorders, cerebellar disorders, spinocerebellardisorders, cognitive disorders, cranial trauma, head trauma, stroke,panic attacks, peripheric neuropathy, glaucoma, migraine, MorbusParkinson, Morbus Huntington, Morbus Alzheimer, Raynaud's disease,tremblement disorders, compulsive disorders, senile dementia, thymicdisorders, tardive dyskinesia, bipolar disorders, medicament-inducedmovement disorders, dystonia, endotoxemic shock, hemorragic shock,hypotension, insomnia, immunologic disorders, sclerotic plaques,vomiting, diarrhea, asthma, memory disorders, pruritus, pain, or forpotentiation of the analgesic effect of narcotic and non-narcoticanalgesics, or for influencing intestinal transit the method comprisingadministering to a patient a compound of claim 1.